chr15-31002948-T-G

Variant names:

• chr15-31002948-T-G
• rs17227996
• NM_001252024.2:c.3752A>C

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.3752A>C​(p.Asn1251Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,601,860 control chromosomes in the GnomAD database, including 2,567 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (194 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2373 hom.)
• Consequence: TRPM1 NM_001252024.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.611
• Publications: 17 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: Labcorp Genetics (formerly Invitae), G2P
• TRPM1-related retinopathy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259720 (HGNC:58477):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012834966).
• BP6: Variant 15-31002948-T-G is Benign according to our data. Variant chr15-31002948-T-G is described in ClinVar as Benign. ClinVar VariationId is 315501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252024.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	NM_001252024.2	MANE Select	c.3752A>C	p.Asn1251Thr	missense	Exon 28 of 28	NP_001238953.1	Q7Z4N2-6
	TRPM1	NM_001252020.2		c.3803A>C	p.Asn1268Thr	missense	Exon 27 of 27	NP_001238949.1	Q7Z4N2-5
	TRPM1	NM_002420.6		c.3686A>C	p.Asn1229Thr	missense	Exon 27 of 27	NP_002411.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	ENST00000256552.11	TSL:1 MANE Select	c.3752A>C	p.Asn1251Thr	missense	Exon 28 of 28	ENSP00000256552.7	Q7Z4N2-6
	TRPM1	ENST00000558445.6	TSL:1	c.3803A>C	p.Asn1268Thr	missense	Exon 27 of 27	ENSP00000452946.2	Q7Z4N2-5
	TRPM1	ENST00000397795.7	TSL:1	c.3686A>C	p.Asn1229Thr	missense	Exon 27 of 27	ENSP00000380897.2	Q7Z4N2-1

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6180 AN: 152184 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0611

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0408 AC: 9929 AN: 243126 AF XY: 0.0409

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0303

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0789

Gnomad NFE exome AF: 0.0595

Gnomad OTH exome AF: 0.0431

GnomAD4 exome AF: 0.0531 AC: 77003 AN: 1449558 Hom.: 2373 Cov.: 34 AF XY: 0.0518 AC XY: 37288 AN XY: 719390

African (AFR) AF: 0.00943 AC: 311 AN: 32978

American (AMR) AF: 0.0225 AC: 976 AN: 43442

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 810 AN: 25656

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39482

South Asian (SAS) AF: 0.00638 AC: 541 AN: 84802

European-Finnish (FIN) AF: 0.0788 AC: 4187 AN: 53122

Middle Eastern (MID) AF: 0.0271 AC: 155 AN: 5712

European-Non Finnish (NFE) AF: 0.0610 AC: 67376 AN: 1104588

Other (OTH) AF: 0.0442 AC: 2643 AN: 59776

GnomAD4 genome AF: 0.0406 AC: 6180 AN: 152302 Hom.: 194 Cov.: 32 AF XY: 0.0397 AC XY: 2959 AN XY: 74462

African (AFR) AF: 0.0112 AC: 464 AN: 41568

American (AMR) AF: 0.0304 AC: 465 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4826

European-Finnish (FIN) AF: 0.0774 AC: 821 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0611 AC: 4153 AN: 68016

Other (OTH) AF: 0.0302 AC: 64 AN: 2116

Alfa AF: 0.0505 Hom.: 749

Bravo AF: 0.0364

TwinsUK AF: 0.0596 AC: 221

ALSPAC AF: 0.0646 AC: 249

ESP6500AA AF: 0.0110 AC: 43

ESP6500EA AF: 0.0607 AC: 503

ExAC AF: 0.0397 AC: 4793

Asia WGS AF: 0.00520 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital stationary night blindness 1C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.61
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.034
Sift	Benign	0.69	T
Sift4G	Benign	0.67	T
Polyphen		0.0010	B
Vest4		0.054
MPC		0.21
ClinPred		0.0047	T
GERP RS		2.8
Varity_R		0.053
gMVP		0.20
Mutation Taster		=94/6	polymorphism (auto)

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: rs17227996; hg19: chr15-31295151;