15-31001868-T-A

Position:

• chr15-31001868-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001252024.2(TRPM1):​c.4832A>T​(p.Glu1611Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.766

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061650306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM1	NM_001252024.2	c.4832A>T	p.Glu1611Val	missense_variant	28/28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2	c.4883A>T	p.Glu1628Val	missense_variant	27/27		NP_001238949.1
TRPM1	NM_002420.6	c.4766A>T	p.Glu1589Val	missense_variant	27/27		NP_002411.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11	c.4832A>T	p.Glu1611Val	missense_variant	28/28	1	NM_001252024.2	ENSP00000256552	P4
	ENST00000665655.1	n.71+9627T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461424 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 24, 2021

This variant has not been reported in the literature in individuals with TRPM1-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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with valine at codon 1589 of the TRPM1 protein (p.Glu1589Val). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.085	T;.;.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.42	N;N;N;N
REVEL	Benign	0.046
Sift	Uncertain	0.024	D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D
Polyphen		0.024	B;.;.;.
Vest4		0.20
MutPred		0.17		Gain of MoRF binding (P = 0.0132);.;.;.;
MVP		0.30
MPC		0.24
ClinPred		0.062	T
GERP RS		0.33
Varity_R		0.084
gMVP		0.29

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: rs2031775195; hg19: chr15-31294071;