rs104894318

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PP2PP3PP5_Very_Strong

The NM_000372.5(TYR):c.1342G>A(p.Asp448Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,459,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D448G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TYR
NM_000372.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 9.40

Publications

7 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: Orphanet, G2P, 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: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.781

PP5

Variant 11-89284930-G-A is Pathogenic according to our data. Variant chr11-89284930-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000372.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	NM_000372.5	MANE Select	c.1342G>A	p.Asp448Asn	missense	Exon 4 of 5	NP_000363.1	P14679-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYR	ENST00000263321.6	TSL:1 MANE Select	c.1342G>A	p.Asp448Asn	missense	Exon 4 of 5	ENSP00000263321.4	P14679-1
	TYR	ENST00000528243.1	TSL:5	n.340G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

250176

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1459570

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1110406

Other (OTH)

AF:

0.0000166

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Oculocutaneous albinism type 1A (2)

Oculocutaneous albinism type 1B (1)

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

SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.78

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PhyloP100

9.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.35

REVEL

Uncertain

0.54

Sift

Benign

0.098

Sift4G

Benign

0.091

Polyphen

0.86

Vest4

0.80

MutPred

0.34

Gain of sheet (P = 0.0827)

MVP

1.0

MPC

0.019

ClinPred

0.65

GERP RS

4.7

Varity_R

0.11

gMVP

0.71

Mutation Taster

=22/78

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over