rs387906562

chr9-12702410-TACAA-T

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.1057_1060del(p.Asn353ValfsTer31) variant causes a frameshift change. The variant allele was found at a frequency of 0.000102 in 1,612,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TYRP1 NM_000550.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.83

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 9-12702410-TACAA-T is Pathogenic according to our data. Variant chr9-12702410-TACAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 17598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-12702410-TACAA-T is described in Lovd as [Pathogenic]. Variant chr9-12702410-TACAA-T is described in Lovd as [Likely_pathogenic]. Variant chr9-12702410-TACAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYRP1	NM_000550.3	c.1057_1060del	p.Asn353ValfsTer31	frameshift_variant	5/8	ENST00000388918.10
LURAP1L-AS1	NR_125775.1	n.317-1788_317-1785del		intron_variant, non_coding_transcript_variant
TYRP1	XM_047423841.1	c.852_855del	p.Thr285PhefsTer10	frameshift_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYRP1	ENST00000388918.10	c.1057_1060del	p.Asn353ValfsTer31	frameshift_variant	5/8	1	NM_000550.3	P1
LURAP1L-AS1	ENST00000417638.1	n.273-1788_273-1785del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000798 AC: 20 AN: 250642 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135460

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1460784 Hom.: 0 AF XY: 0.000121 AC XY: 88 AN XY: 726688

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74278

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000416

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2023	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: 18821858, 19533799, 34426522, 31589614) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change creates a premature translational stop signal (p.Asn353Valfs*31) 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 (rs752724988, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 18821858, 19533799). ClinVar contains an entry for this variant (Variation ID: 17598). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Oculocutaneous albinism type 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 04, 2014	The Asn353ValfsX31 variant in TYRP1 has been reported in 1 Asian individual with oculocutaneous albinism type III (compound heterozygous) (Rooryck 2008). The Asn353ValfsX31 variant was not identified in large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 353 and lead to a premature termination codon 31 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. _x000D_In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) for oculocutaneous albinism type III acting in a recessive manner. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -

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

Nov 04, 2021

- -

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: rs387906562; hg19: chr9-12702410;