rs34509359

chr9-12694255-C-Achr9-12694255-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000550.3(TYRP1):c.259C>A(p.Arg87=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0543 in 1,613,566 control chromosomes in the GnomAD database, including 2,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R87R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.043 (188 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2514 hom.)
• Consequence: TYRP1 NM_000550.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 9-12694255-C-A is Benign according to our data. Variant chr9-12694255-C-A is described in ClinVar as [Benign]. Clinvar id is 256644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYRP1	NM_000550.3	c.259C>A	p.Arg87=	synonymous_variant	2/8	ENST00000388918.10
TYRP1	XM_047423841.1	c.259C>A	p.Arg87=	synonymous_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYRP1	ENST00000388918.10	c.259C>A	p.Arg87=	synonymous_variant	2/8	1	NM_000550.3	P1
TYRP1	ENST00000473763.1	c.259C>A	p.Arg87=	synonymous_variant	2/2	4
TYRP1	ENST00000459790.1	n.514C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0430 AC: 6545 AN: 152068 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0620

Gnomad OTH AF: 0.0454

GnomAD3 exomes AF: 0.0450 AC: 11227 AN: 249496 Hom.: 325 AF XY: 0.0449 AC XY: 6053 AN XY: 134846

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0235

Gnomad ASJ exome AF: 0.0682

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0146

Gnomad FIN exome AF: 0.0813

Gnomad NFE exome AF: 0.0626

Gnomad OTH exome AF: 0.0513

GnomAD4 exome AF: 0.0555 AC: 81055 AN: 1461382 Hom.: 2514 Cov.: 31 AF XY: 0.0542 AC XY: 39436 AN XY: 726934

Gnomad4 AFR exome AF: 0.00995

Gnomad4 AMR exome AF: 0.0246

Gnomad4 ASJ exome AF: 0.0714

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.0800

Gnomad4 NFE exome AF: 0.0620

Gnomad4 OTH exome AF: 0.0510

GnomAD4 genome AF: 0.0430 AC: 6544 AN: 152184 Hom.: 188 Cov.: 32 AF XY: 0.0432 AC XY: 3213 AN XY: 74390

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.0299

Gnomad4 ASJ AF: 0.0755

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0839

Gnomad4 NFE AF: 0.0620

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0488 Hom.: 91

Bravo AF: 0.0386

Asia WGS AF: 0.00635 AC: 23 AN: 3478

EpiCase AF: 0.0589

EpiControl AF: 0.0614

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Oculocutaneous albinism type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Benign	12
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs34509359; hg19: chr9-12694255; COSMIC: COSV66357970; COSMIC: COSV66357970;