rs142170797

Variant names:

• chr11-89191297-C-A
• rs142170797
• NM_000372.5:c.915C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BS2_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8
• Conservation: PhyloP100: 0.723

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]

ACMG classification

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

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 minimal pigment oculocutaneous albinism type 1, temperature-sensitive oculocutaneous albinism type 1, oculocutaneous albinism type 1B, oculocutaneous albinism type 1, oculocutaneous albinism type 1A.
• BS2: High Homozygotes in GnomAdExome4 at 3 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	c.915C>A	p.Asp305Glu	missense_variant	Exon 2 of 5	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	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	c.915C>A	p.Asp305Glu	missense_variant	Exon 2 of 5	1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000526139.1	n.976C>A		non_coding_transcript_exon_variant	Exon 2 of 3	1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152068 Hom.: 0 Cov.: 32

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: 75 AN: 251188 AF XY: 0.000324

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.: 3 Cov.: 31 AF XY: 0.000406 AC XY: 295 AN XY: 727046

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33448

Gnomad4 AMR exome AF: 0.000179 AC: 8 AN: 44670

Gnomad4 ASJ exome AF: 0.000230 AC: 6 AN: 26116

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39690

Gnomad4 SAS exome AF: 0.000522 AC: 45 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53412

Gnomad4 NFE exome AF: 0.000386 AC: 429 AN: 1111780

Gnomad4 Remaining exome AF: 0.000480 AC: 29 AN: 60372

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74412

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240767 AN: 0.0000240767

Gnomad4 AMR AF: 0.000328 AC: 0.000327568 AN: 0.000327568

Gnomad4 ASJ AF: 0.000288 AC: 0.000288018 AN: 0.000288018

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000622 AC: 0.000622148 AN: 0.000622148

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000294 AC: 0.000294074 AN: 0.000294074

Gnomad4 OTH AF: 0.000475 AC: 0.000474834 AN: 0.000474834

Alfa AF: 0.000364 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

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. -

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) -

Oculocutaneous albinism type 1A Pathogenic:1 Uncertain: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	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.67
Sift	Benign	0.067	T
Sift4G	Benign	0.078	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.55		Gain of methylation at K306 (P = 0.0793);
MVP		0.99
MPC		0.075
ClinPred		0.11	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.77
Mutation Taster		=18/82	disease causing (ClinVar)

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

LitVar

Other links and lift over

dbSNP: rs142170797; hg19: chr11-88924465;