9-12694024-G-C

Variant names:

• chr9-12694024-G-C
• NM_000550.3:c.28G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000550.3(TYRP1):​c.28G>C​(p.Gly10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TYRP1 NM_000550.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.336

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYRP1	NM_000550.3	c.28G>C	p.Gly10Arg	missense_variant	Exon 2 of 8	ENST00000388918.10	NP_000541.1
TYRP1	XM_047423841.1	c.28G>C	p.Gly10Arg	missense_variant	Exon 2 of 5		XP_047279797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYRP1	ENST00000388918.10	c.28G>C	p.Gly10Arg	missense_variant	Exon 2 of 8	1	NM_000550.3	ENSP00000373570.4
TYRP1	ENST00000473763.1	c.28G>C	p.Gly10Arg	missense_variant	Exon 2 of 2	4		ENSP00000419006.1
TYRP1	ENST00000459790.1	n.283G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 10 of the TYRP1 protein (p.Gly10Arg). This variant has not been reported in the literature in individuals affected with TYRP1-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	7.4
DANN	Benign	0.96
DEOGEN2	Benign	0.088	T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.52	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.6	.;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.085	T;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.26	.;B
Vest4		0.19
MutPred		0.74		Loss of ubiquitination at K5 (P = 0.0449);Loss of ubiquitination at K5 (P = 0.0449);
MVP		0.97
MPC		0.0064
ClinPred		0.12	T
GERP RS		0.94
Varity_R		0.074
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-12694024;