rs2762464

Variant names:

• chr9-12709586-A-T
• rs2762464
• NM_000550.3:c.*404A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000550.3(TYRP1):​c.*404A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 184,574 control chromosomes in the GnomAD database, including 25,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (20460 hom., cov: 32)
  • Exomes 𝑓: 0.51 (5186 hom.)
• Consequence: TYRP1 NM_000550.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.623
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-12709586-A-T is Benign according to our data. Variant chr9-12709586-A-T is described in ClinVar as Benign. ClinVar VariationId is 364865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYRP1	NM_000550.3	c.*404A>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000388918.10	NP_000541.1
LURAP1L-AS1	NR_125775.1	n.317-8960T>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYRP1	ENST00000388918.10	c.*404A>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_000550.3	ENSP00000373570.4

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69687 AN: 151660 Hom.: 20460 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.536

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.465

GnomAD4 exome AF: 0.508 AC: 16657 AN: 32798 Hom.: 5186 Cov.: 0 AF XY: 0.483 AC XY: 8307 AN XY: 17208

African (AFR) AF: 0.116 AC: 119 AN: 1024

American (AMR) AF: 0.439 AC: 1411 AN: 3216

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 397 AN: 800

East Asian (EAS) AF: 0.00718 AC: 20 AN: 2784

South Asian (SAS) AF: 0.240 AC: 960 AN: 3994

European-Finnish (FIN) AF: 0.710 AC: 985 AN: 1388

Middle Eastern (MID) AF: 0.478 AC: 44 AN: 92

European-Non Finnish (NFE) AF: 0.660 AC: 11870 AN: 17992

Other (OTH) AF: 0.564 AC: 851 AN: 1508

GnomAD4 genome AF: 0.459 AC: 69686 AN: 151776 Hom.: 20460 Cov.: 32 AF XY: 0.453 AC XY: 33573 AN XY: 74184

African (AFR) AF: 0.155 AC: 6415 AN: 41474

American (AMR) AF: 0.408 AC: 6208 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 1856 AN: 3464

East Asian (EAS) AF: 0.0111 AC: 57 AN: 5146

South Asian (SAS) AF: 0.232 AC: 1121 AN: 4822

European-Finnish (FIN) AF: 0.709 AC: 7491 AN: 10570

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.663 AC: 44964 AN: 67776

Other (OTH) AF: 0.461 AC: 972 AN: 2110

Alfa AF: 0.561 Hom.: 3342

Bravo AF: 0.428

Asia WGS AF: 0.134 AC: 467 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oculocutaneous albinism type 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.65
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2762464; hg19: chr9-12709586; COSMIC: COSV66357980; COSMIC: COSV66357980;