9-12694063-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_000550.3(TYRP1):c.67C>T(p.Arg23Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,613,952 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: TYRP1 NM_000550.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.108

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0048153102).
• BP6: Variant 9-12694063-C-T is Benign according to our data. Variant chr9-12694063-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 913604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYRP1	NM_000550.3	c.67C>T	p.Arg23Trp	missense_variant	2/8	ENST00000388918.10
TYRP1	XM_047423841.1	c.67C>T	p.Arg23Trp	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYRP1	ENST00000388918.10	c.67C>T	p.Arg23Trp	missense_variant	2/8	1	NM_000550.3	P1
TYRP1	ENST00000473763.1	c.67C>T	p.Arg23Trp	missense_variant	2/2	4
TYRP1	ENST00000459790.1	n.322C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000803 AC: 122 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000621 AC: 156 AN: 251050 Hom.: 0 AF XY: 0.000649 AC XY: 88 AN XY: 135660

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.000767

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000758 AC: 1108 AN: 1461874 Hom.: 1 Cov.: 31 AF XY: 0.000752 AC XY: 547 AN XY: 727230

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.000847

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000802 AC: 122 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.000955 AC XY: 71 AN XY: 74332

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.000918

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000848 Hom.: 1

Bravo AF: 0.000631

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000642 AC: 78

EpiCase AF: 0.000436

EpiControl AF: 0.00130

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oculocutaneous albinism type 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	3.9
Dann	Benign	0.48
DEOGEN2	Benign	0.063	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.095	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Uncertain	0.39	D
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.86	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.56	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0020	.;B
Vest4		0.11
MVP		0.84
MPC		0.0057
ClinPred		0.0017	T
GERP RS		-1.7
Varity_R		0.037
gMVP		0.56

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: rs141834891; hg19: chr9-12694063; COSMIC: COSV66358546; COSMIC: COSV66358546;