NM_001252024.2:c.4-71G>A

Variant names:

• chr15-31077055-C-T
• rs4779818
• NM_001252024.2:c.4-71G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001252024.2(TRPM1):​c.4-71G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 992,454 control chromosomes in the GnomAD database, including 114,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17811 hom., cov: 33)
  • Exomes 𝑓: 0.47 (96977 hom.)
• Consequence: TRPM1 NM_001252024.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.60
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-31077055-C-T is Benign according to our data. Variant chr15-31077055-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM1	NM_001252024.2	c.4-71G>A		intron_variant	Intron 2 of 27	ENST00000256552.11	NP_001238953.1
TRPM1	NM_001252020.2	c.55-71G>A		intron_variant	Intron 1 of 26		NP_001238949.1
TRPM1	NM_002420.6	c.-63-71G>A		intron_variant	Intron 1 of 26		NP_002411.3
TRPM1	NM_001252030.2	c.-63-71G>A		intron_variant	Intron 1 of 2		NP_001238959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM1	ENST00000256552.11	c.4-71G>A		intron_variant	Intron 2 of 27	1	NM_001252024.2	ENSP00000256552.7

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72648 AN: 151994 Hom.: 17802 Cov.: 33

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.483

GnomAD4 exome AF: 0.472 AC: 396781 AN: 840342 Hom.: 96977 AF XY: 0.468 AC XY: 206435 AN XY: 440666

African (AFR) AF: 0.466 AC: 9852 AN: 21158

American (AMR) AF: 0.472 AC: 18602 AN: 39408

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 8497 AN: 21910

East Asian (EAS) AF: 0.781 AC: 27773 AN: 35560

South Asian (SAS) AF: 0.409 AC: 29332 AN: 71676

European-Finnish (FIN) AF: 0.553 AC: 24946 AN: 45134

Middle Eastern (MID) AF: 0.440 AC: 2022 AN: 4598

European-Non Finnish (NFE) AF: 0.458 AC: 256775 AN: 561002

Other (OTH) AF: 0.476 AC: 18982 AN: 39896

GnomAD4 genome AF: 0.478 AC: 72691 AN: 152112 Hom.: 17811 Cov.: 33 AF XY: 0.482 AC XY: 35836 AN XY: 74342

African (AFR) AF: 0.464 AC: 19228 AN: 41478

American (AMR) AF: 0.466 AC: 7128 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1345 AN: 3462

East Asian (EAS) AF: 0.775 AC: 4017 AN: 5180

South Asian (SAS) AF: 0.432 AC: 2082 AN: 4824

European-Finnish (FIN) AF: 0.569 AC: 6008 AN: 10568

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31366 AN: 67990

Other (OTH) AF: 0.482 AC: 1017 AN: 2112

Alfa AF: 0.466 Hom.: 24321

Bravo AF: 0.475

Asia WGS AF: 0.556 AC: 1932 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.49
PhyloP100		-1.6
Mutation Taster		=11/89	disease causing

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: rs4779818; hg19: chr15-31369258; COSMIC: COSV56632243;