rs138886378

Positions:

• chr15-31067145-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP4_Strong BS1 BS2

The NM_001252024.2(TRPM1):​c.536C>T​(p.Ser179Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,614,100 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (26 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 9.99

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 Benign. Variant got -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011376858).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00382 (581/152246) while in subpopulation NFE AF= 0.00616 (419/68020). AF 95% confidence interval is 0.00567. There are 3 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM1	NM_001252024.2	c.536C>T	p.Ser179Phe	missense_variant	6/28	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2	c.587C>T	p.Ser196Phe	missense_variant	5/27		NP_001238949.1
TRPM1	NM_002420.6	c.470C>T	p.Ser157Phe	missense_variant	5/27		NP_002411.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11	c.536C>T	p.Ser179Phe	missense_variant	6/28	1	NM_001252024.2	ENSP00000256552.7

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 581 AN: 152128 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00323 AC: 806 AN: 249574 Hom.: 2 AF XY: 0.00316 AC XY: 428 AN XY: 135402

Gnomad AFR exome AF: 0.000839

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.00531

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.00436 AC: 6376 AN: 1461854 Hom.: 26 Cov.: 33 AF XY: 0.00436 AC XY: 3174 AN XY: 727228

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00462

Gnomad4 NFE exome AF: 0.00520

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00382 AC: 581 AN: 152246 Hom.: 3 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74458

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.00616

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00497 Hom.: 9

Bravo AF: 0.00329

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00316 AC: 26

ExAC AF: 0.00319 AC: 385

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TRPM1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2013	- -

Congenital stationary night blindness 1C Uncertain:1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

TRPM1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;.;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.91
MVP		0.47
MPC		0.84
ClinPred		0.057	T
GERP RS		6.1
Varity_R		0.63
gMVP		0.57

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: rs138886378; hg19: chr15-31359348;