rs387906560

chr9-12704544-GA-Gchr9-12704544-GA-GAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000550.3(TYRP1):c.1103del(p.Lys368SerfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,612,526 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G367G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TYRP1 NM_000550.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.340

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 18 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 9-12704544-GA-G is Pathogenic according to our data. Variant chr9-12704544-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-12704544-GA-G is described in Lovd as [Pathogenic]. Variant chr9-12704544-GA-G is described in Lovd as [Likely_pathogenic]. Variant chr9-12704544-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYRP1	NM_000550.3	c.1103del	p.Lys368SerfsTer17	frameshift_variant	6/8	ENST00000388918.10
LURAP1L-AS1	NR_125775.1	n.317-3919del		intron_variant, non_coding_transcript_variant
TYRP1	XM_047423841.1	c.898del	p.Ser300ValfsTer2	frameshift_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYRP1	ENST00000388918.10	c.1103del	p.Lys368SerfsTer17	frameshift_variant	6/8	1	NM_000550.3	P1
LURAP1L-AS1	ENST00000417638.1	n.273-3919del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 151998 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000355 AC: 89 AN: 250536 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135444

Gnomad AFR exome AF: 0.00506

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1460410 Hom.: 0 Cov.: 32 AF XY: 0.0000785 AC XY: 57 AN XY: 726524

Gnomad4 AFR exome AF: 0.00407

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152116 Hom.: 1 Cov.: 31 AF XY: 0.00151 AC XY: 112 AN XY: 74364

Gnomad4 AFR AF: 0.00503

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.00161

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2022	In vitro studies in cultured fibroblasts from an affected individual homozygous for the c.1103delA variant showed absent TYRP1 mRNA and protein (Boissy et al., 1996); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33438000, 21996312, 28041643, 24845642, 31589614, 32581362, 9345097, 8651291) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Lys368Serfs*17) 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 (rs534275065, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 8651291, 9345097). ClinVar contains an entry for this variant (Variation ID: 17593). For these reasons, this variant has been classified as Pathogenic. -

Oculocutaneous albinism type 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 13, 2021	PVS1, PM3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1997	- -

Oculocutaneous albinism type 3;C2677086:Skin/hair/eye pigmentation, variation in, 11 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 17, 2021

- -

Albinism Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

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: rs387906560; hg19: chr9-12704544;