rs121912778

chr9-12704564-C-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.1120C>T(p.Arg374Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,612,786 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R374R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: TYRP1 NM_000550.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.01

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]

LURAP1L-AS1 (HGNC:49761): (LURAP1L antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-12704564-C-T is Pathogenic according to our data. Variant chr9-12704564-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17595.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-12704564-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYRP1	NM_000550.3	c.1120C>T	p.Arg374Ter	stop_gained	6/8	ENST00000388918.10
LURAP1L-AS1	NR_125775.1	n.317-3938G>A		intron_variant, non_coding_transcript_variant
TYRP1	XM_047423841.1	c.915C>T	p.Phe305=	synonymous_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYRP1	ENST00000388918.10	c.1120C>T	p.Arg374Ter	stop_gained	6/8	1	NM_000550.3	P1
LURAP1L-AS1	ENST00000417638.1	n.273-3938G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250744 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135550

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1460800 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 726708

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151986 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74252

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Oculocutaneous albinism type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2005

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

This sequence change creates a premature translational stop signal (p.Arg374*) in the TYRP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TYRP1 are known to be pathogenic (PMID: 8651291, 9345097). This variant is present in population databases (rs121912778, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism type 3 (PMID: 15996218). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R373X (c.1117C>T). ClinVar contains an entry for this variant (Variation ID: 17595). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	43
Dann	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.54	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.98
GERP RS		5.5

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: rs121912778; hg19: chr9-12704564; COSMIC: COSV66357901; COSMIC: COSV66357901;