rs4779816

Variant names:

• chr15-31076920-A-C
• rs4779816
• ENST00000397795.7:c.2T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-31076920-A-C
• chr15-31076920-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The ENST00000397795.7(TRPM1):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TRPM1 ENST00000397795.7 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• Publications: 41 publications found

Genes affected

TRPM1 (HGNC:7146): (transient receptor potential cation channel subfamily M member 1) This gene encodes a member of the transient receptor potential melastatin subfamily of transient receptor potential ion channels. The encoded protein is a calcium permeable cation channel that is expressed in melanocytes and may play a role in melanin synthesis. Specific mutations in this gene are the cause autosomal recessive complete congenital stationary night blindness-1C. The expression of this protein is inversely correlated with melanoma aggressiveness and as such it is used as a prognostic marker for melanoma metastasis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

TRPM1 Gene-Disease associations (from GenCC):

• congenital stationary night blindness 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• TRPM1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 71 codons. Genomic position: 31070033. Lost 0.044 part of the original CDS.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM1	NM_001252024.2	c.68T>G	p.Met23Arg	missense_variant	Exon 3 of 28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_002420.6	c.2T>G	p.Met1?	start_lost	Exon 2 of 27		NP_002411.3
TRPM1	NM_001252030.2	c.2T>G	p.Met1?	start_lost	Exon 2 of 3		NP_001238959.1
TRPM1	NM_001252020.2	c.119T>G	p.Met40Arg	missense_variant	Exon 2 of 27		NP_001238949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11	c.68T>G	p.Met23Arg	missense_variant	Exon 3 of 28	1	NM_001252024.2	ENSP00000256552.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1456434 Hom.: 0 Cov.: 34 AF XY: 0.00000552 AC XY: 4 AN XY: 724964

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1107126

Other (OTH) AF: 0.00 AC: 0 AN: 60212

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 174863

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.10	T;.;.;T;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.073	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
PhyloP100		-0.046
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.86	N;N;N;N;N;N
REVEL	Benign	0.094
Sift	Uncertain	0.015	D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D
Polyphen		0.0050	B;.;.;.;.;.
Vest4		0.17
MutPred		0.93		Loss of ubiquitination at K2 (P = 0.0168);.;.;Loss of ubiquitination at K2 (P = 0.0168);Loss of ubiquitination at K2 (P = 0.0168);Loss of ubiquitination at K2 (P = 0.0168);
MVP		0.21
MPC		0.32
ClinPred		0.67	D
GERP RS		2.4
Varity_R		0.30
gMVP		0.25
Mutation Taster		=108/92	polymorphism

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: rs4779816; hg19: chr15-31369123;