chr9-12693999-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000550.3(TYRP1):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TYRP1
NM_000550.3 start_lost

Scores

7
3
6

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.95
Variant links:
Genes affected
TYRP1 (HGNC:12450): (tyrosinase related protein 1) This gene encodes a melanosomal enzyme that belongs to the tyrosinase family and plays an important role in the melanin biosynthetic pathway. Defects in this gene are the cause of rufous oculocutaneous albinism and oculocutaneous albinism type III. [provided by RefSeq, Mar 2009]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-12693999-G-T is Pathogenic according to our data. Variant chr9-12693999-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2714033.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TYRP1NM_000550.3 linkuse as main transcriptc.3G>T p.Met1? start_lost 2/8 ENST00000388918.10
TYRP1XM_047423841.1 linkuse as main transcriptc.3G>T p.Met1? start_lost 2/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TYRP1ENST00000388918.10 linkuse as main transcriptc.3G>T p.Met1? start_lost 2/81 NM_000550.3 P1
TYRP1ENST00000473763.1 linkuse as main transcriptc.3G>T p.Met1? start_lost 2/24
TYRP1ENST00000459790.1 linkuse as main transcriptn.258G>T non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change affects the initiator methionine of the TYRP1 mRNA. The next in-frame methionine is located at codon 40. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TYRP1-related conditions. This variant disrupts a region of the TYRP1 protein in which other variant(s) (p.Pro27Arg) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.25
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
T;T
Eigen
Benign
-0.078
Eigen_PC
Benign
0.031
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.86
D
MutationTaster
Benign
1.0
D;D
PROVEAN
Benign
-0.68
N;N
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.14
.;B
Vest4
0.68
MutPred
0.99
Gain of catalytic residue at L6 (P = 0.0244);Gain of catalytic residue at L6 (P = 0.0244);
MVP
1.0
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.87
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-12693999; COSMIC: COSV101141145; COSMIC: COSV101141145; API