9-12693999-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.95

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]

ACMG classification

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
TYRP1	NM_000550.3	c.3G>T	p.Met1?	start_lost	2/8	ENST00000388918.10
TYRP1	XM_047423841.1	c.3G>T	p.Met1?	start_lost	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYRP1	ENST00000388918.10	c.3G>T	p.Met1?	start_lost	2/8	1	NM_000550.3	P1
TYRP1	ENST00000473763.1	c.3G>T	p.Met1?	start_lost	2/2	4
TYRP1	ENST00000459790.1	n.258G>T		non_coding_transcript_exon_variant	2/2	2

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

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This 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;