rs387906562

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000550.3(TYRP1):c.1057_1060delAACA(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 Likely 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.83

Publications

14 publications found

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]

TYRP1 links:

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

LURAP1L-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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/Likely_pathogenic. ClinVar VariationId is 17598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYRP1	NM_000550.3 link	c.1057_1060delAACA	p.Asn353ValfsTer31	frameshift_variant	Exon 5 of 8	ENST00000388918.10	NP_000541.1	P17643
TYRP1	XM_047423841.1 link	c.852_855delAACA	p.Thr285PhefsTer10	frameshift_variant	Exon 4 of 5		XP_047279797.1
LURAP1L-AS1	NR_125775.1 link	n.317-1788_317-1785delTTGT		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYRP1	ENST00000388918.10 link	c.1057_1060delAACA	p.Asn353ValfsTer31	frameshift_variant	Exon 5 of 8	1	NM_000550.3	ENSP00000373570.4		P17643

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000798

AC:

AN:

250642

AF XY:

0.000103

show subpopulations

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 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.:

AF XY:

0.000121

AC XY:

AN XY:

726688

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33430

American (AMR)

AF:

0.0000224

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000162

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000114

AC:

127

AN:

1111336

Other (OTH)

AF:

0.0000995

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000416

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 22, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Oculocutaneous albinism type 3

Pathogenic:3

Aug 01, 2024

Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The c.1057_1060del, p.Asn353Valfs*31, variant found is located in exon 5 of the TYRP1 gene. The gene is haploinsufficient and as a consequence of this variant there would be no translation and consequently, a lack of protein (PVS1). Loss-of-function variants are known to be a mechanism of pathogenicity in this gene (70 pathogenic null variants reported in ClinVar). The variant is associated with an autosomal recessive type of inheritance and was reported in the literature in trans with another pathogenic variant (PM3). The variant found is found at very low frequency in population databases such as GnomAD, ExAc or 1000 genomes (PM2_Supporting) and has been reported as pathogenic in ClinVar (rs387906562) related to oculocutaneous albinism type 3 (OCA3) (OMIM #203290), an autosomal recessive inheritance pathology that affects melanin biosynthesis and leads to reduced pigmentation in hair, skin and eyes. The patient's phenotype is consistent with oculocutaneous albinism type 3, and the TYRP1 gene is closely associated with the condition (PP4). Patient with albinism. -

Jul 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 04, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

TYRP1-related disorder

Pathogenic:1

Apr 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TYRP1 c.1057_1060delAACA variant is predicted to result in a frameshift and premature protein termination (p.Asn353Valfs*31). This variant has been reported in individuals with oculocutaneous albinism (Rooryck et al. 2008. PubMed ID: 18821858; Chiang et al. 2009. PubMed ID: 19533799). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in TYRP1 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -

Oculocutaneous albinism type 3;C2677086:MELANESIAN BLOND HAIR

Pathogenic:1

Nov 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.8

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over