chr15-31076920-A-G

Position:

• chr15-31076920-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 10P and 16B. PVS1 PS1_Moderate BP6_Very_Strong BA1

The ENST00000397795.7(TRPM1):​c.2T>C​(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 0.821 in 1,606,726 control chromosomes in the GnomAD database, including 544,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55463 hom., cov: 32)
  • Exomes 𝑓: 0.82 (488662 hom.)
• Consequence: TRPM1 ENST00000397795.7 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0460

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000397795.7 (TRPM1) was described as [Likely_pathogenic] in ClinVar as 191053
• BP6: Variant 15-31076920-A-G is Benign according to our data. Variant chr15-31076920-A-G is described in ClinVar as [Benign]. Clinvar id is 315540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-31076920-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM1	NM_001252024.2	c.68T>C	p.Met23Thr	missense_variant	3/28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_002420.6	c.2T>C	p.Met1?	start_lost	2/27		NP_002411.3
TRPM1	NM_001252030.2	c.2T>C	p.Met1?	start_lost	2/3		NP_001238959.1
TRPM1	NM_001252020.2	c.119T>C	p.Met40Thr	missense_variant	2/27		NP_001238949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11	c.68T>C	p.Met23Thr	missense_variant	3/28	1	NM_001252024.2	ENSP00000256552	P4

Frequencies

GnomAD3 genomes AF: 0.852 AC: 129532 AN: 152054 Hom.: 55414 Cov.: 32

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.874

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.977

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.811

Gnomad OTH AF: 0.838

GnomAD3 exomes AF: 0.848 AC: 211620 AN: 249508 Hom.: 90241 AF XY: 0.843 AC XY: 114156 AN XY: 135378

Gnomad AFR exome AF: 0.903

Gnomad AMR exome AF: 0.912

Gnomad ASJ exome AF: 0.851

Gnomad EAS exome AF: 0.984

Gnomad SAS exome AF: 0.863

Gnomad FIN exome AF: 0.811

Gnomad NFE exome AF: 0.803

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.818 AC: 1190110 AN: 1454554 Hom.: 488662 Cov.: 34 AF XY: 0.819 AC XY: 593133 AN XY: 724094

Gnomad4 AFR exome AF: 0.905

Gnomad4 AMR exome AF: 0.908

Gnomad4 ASJ exome AF: 0.848

Gnomad4 EAS exome AF: 0.970

Gnomad4 SAS exome AF: 0.861

Gnomad4 FIN exome AF: 0.811

Gnomad4 NFE exome AF: 0.802

Gnomad4 OTH exome AF: 0.835

GnomAD4 genome AF: 0.852 AC: 129637 AN: 152172 Hom.: 55463 Cov.: 32 AF XY: 0.854 AC XY: 63508 AN XY: 74368

Gnomad4 AFR AF: 0.902

Gnomad4 AMR AF: 0.874

Gnomad4 ASJ AF: 0.854

Gnomad4 EAS AF: 0.977

Gnomad4 SAS AF: 0.871

Gnomad4 FIN AF: 0.811

Gnomad4 NFE AF: 0.811

Gnomad4 OTH AF: 0.837

Alfa AF: 0.818 Hom.: 122623

Bravo AF: 0.858

TwinsUK AF: 0.790 AC: 2930

ALSPAC AF: 0.798 AC: 3074

ESP6500AA AF: 0.892 AC: 3317

ESP6500EA AF: 0.801 AC: 6581

ExAC AF: 0.845 AC: 102011

Asia WGS AF: 0.912 AC: 3171 AN: 3478

EpiCase AF: 0.810

EpiControl AF: 0.805

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital stationary night blindness 1C Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.8
DANN	Benign	0.87
DEOGEN2	Benign	0.064	T;.;.;T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.014	N
LIST_S2	Uncertain	0.90	D;T;T;D;D;D
MetaRNN	Benign	8.5e-7	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.0	P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.4	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.068	T;T;T;D;T;D
Sift4G	Benign	0.088	T;T;T;D;T;D
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.049
MPC		0.24
ClinPred		0.0018	T
GERP RS		2.4
Varity_R		0.066
gMVP		0.13

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: rs4779816; hg19: chr15-31369123;