rs142170797

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BS2_Supporting

The NM_000372.5(TYR):c.915C>A(p.Asp305Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,613,694 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D305N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 3 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 0.723

Publications

2 publications found

Variant links:

Genes affected

TYR (HGNC:12442): (tyrosinase) The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]

TYR Gene-Disease associations (from GenCC):

oculocutaneous albinism type 1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
oculocutaneous albinism type 1A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
Waardenburg syndrome type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
minimal pigment oculocutaneous albinism type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
oculocutaneous albinism type 1B
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
temperature-sensitive oculocutaneous albinism type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TYR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000372.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 116 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: -1.9514 (below the threshold of 3.09). Trascript score misZ: -0.85521 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 2, oculocutaneous albinism type 1A, oculocutaneous albinism type 1, oculocutaneous albinism type 1B, minimal pigment oculocutaneous albinism type 1, temperature-sensitive oculocutaneous albinism type 1.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5 link	c.915C>A	p.Asp305Glu	missense_variant	Exon 2 of 5	ENST00000263321.6	NP_000363.1	P14679-1L8B082
TYR	XM_011542970.3 link	c.915C>A	p.Asp305Glu	missense_variant	Exon 2 of 6		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6 link	c.915C>A	p.Asp305Glu	missense_variant	Exon 2 of 5	1	NM_000372.5	ENSP00000263321.4		P14679-1
TYR	ENST00000526139.1 link	n.976C>A		non_coding_transcript_exon_variant	Exon 2 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000299

AC:

AN:

251188

AF XY:

0.000324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000440

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000363

AC:

531

AN:

1461508

Hom.:

Cov.:

AF XY:

0.000406

AC XY:

295

AN XY:

727046

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33448

American (AMR)

AF:

0.000179

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000522

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000386

AC:

429

AN:

1111780

Other (OTH)

AF:

0.000480

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41534

American (AMR)

AF:

0.000328

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68010

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000655

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TYR: PM5, PM2:Supporting -

Oct 18, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26764160, 34426522, 30868138, 21906913, 19060277, 34008892, 30679655, 27734839, 13680365) -

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 305 of the TYR protein (p.Asp305Glu). This variant is present in population databases (rs142170797, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of ocular albinism (PMID: 13680365, 19060277, 27734839, 34008892). ClinVar contains an entry for this variant (Variation ID: 418532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TYR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oculocutaneous albinism type 1A

Pathogenic:1Uncertain:1

May 10, 2018

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4,PM1,PP2,PP3 -

Jul 22, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TYR c.915C>A (p.Asp305Glu) results in a conservative amino acid change located in the copper-binding domain (IPR002227) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 1606724 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in TYR causing Oculocutaneous Albinism (0.0056), allowing no conclusion about variant significance. c.915C>A has been reported in the literature in compound heterozygous state together with a second pathogenic variant, in an affected individual (with dermatological abnormalities), however no further phenotype details were provided (Marinakis_2021). In addition, the variant was also reported in heterozygous state in individuals affected with Oculocutaneous Albinism in whom a second (likely) pathogenic mutation was not identified (e.g. King_2003, Gronskov_2009, Mauri_2016), and was also reported in unaffected controls (Hu_011, Dopazo_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 13680365, 19060277, 21906913, 27734839, 26764160, 34008892). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Oculocutaneous albinism

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A

Uncertain:1

May 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculocutaneous albinism type 1B;C2677190:SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN;C4551504:Oculocutaneous albinism type 1A;CN028925:Ocular albinism with congenital sensorineural hearing loss

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.73

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.7

PhyloP100

0.72

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.67

Sift

Benign

0.067

Sift4G

Benign

0.078

Polyphen

1.0

Vest4

0.84

MutPred

0.55

Gain of methylation at K306 (P = 0.0793);

MVP

0.99

MPC

0.075

ClinPred

0.11

GERP RS

2.7

Varity_R

0.11

gMVP

0.77

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over