ENST00000558445.6:c.16C>T

Variant names:

• chr15-31160944-G-A
• rs75638145
• ENST00000558445.6:c.16C>T
• TRPM1 p.Arg6Trp

Variant summary

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

The ENST00000558445.6(TRPM1):​c.16C>T​(p.Arg6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,534,778 control chromosomes in the GnomAD database, including 15,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1047 hom., cov: 33)
  • Exomes 𝑓: 0.14 (13960 hom.)
• Consequence: TRPM1 ENST00000558445.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.33
• Publications: 9 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 (MetaRNN=0.003954917).
• BP6: Variant 15-31160944-G-A is Benign according to our data. Variant chr15-31160944-G-A is described in ClinVar as Benign. ClinVar VariationId is 1297788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000558445.6. 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_001252020.2		c.16C>T	p.Arg6Trp	missense	Exon 1 of 27	NP_001238949.1	Q7Z4N2-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM1	ENST00000558445.6	TSL:1	c.16C>T	p.Arg6Trp	missense	Exon 1 of 27	ENSP00000452946.2	Q7Z4N2-5
	TRPM1	ENST00000559177.6	TSL:5	c.16C>T	p.Arg6Trp	missense	Exon 1 of 8	ENSP00000453477.2	H0YM61

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15999 AN: 152152 Hom.: 1049 Cov.: 33

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0963

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0581

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.102 AC: 13117 AN: 128012 AF XY: 0.103

Gnomad AFR exome AF: 0.0414

Gnomad AMR exome AF: 0.0859

Gnomad ASJ exome AF: 0.0985

Gnomad EAS exome AF: 0.0181

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.136 AC: 187827 AN: 1382506 Hom.: 13960 Cov.: 32 AF XY: 0.134 AC XY: 91470 AN XY: 682198

African (AFR) AF: 0.0431 AC: 1361 AN: 31584

American (AMR) AF: 0.0892 AC: 3183 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 2379 AN: 25168

East Asian (EAS) AF: 0.0125 AC: 445 AN: 35734

South Asian (SAS) AF: 0.0729 AC: 5775 AN: 79214

European-Finnish (FIN) AF: 0.167 AC: 5595 AN: 33460

Middle Eastern (MID) AF: 0.146 AC: 833 AN: 5688

European-Non Finnish (NFE) AF: 0.149 AC: 160881 AN: 1078112

Other (OTH) AF: 0.127 AC: 7375 AN: 57860

GnomAD4 genome AF: 0.105 AC: 15990 AN: 152272 Hom.: 1047 Cov.: 33 AF XY: 0.105 AC XY: 7804 AN XY: 74442

African (AFR) AF: 0.0463 AC: 1925 AN: 41568

American (AMR) AF: 0.109 AC: 1674 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0963 AC: 334 AN: 3470

East Asian (EAS) AF: 0.0155 AC: 80 AN: 5176

South Asian (SAS) AF: 0.0580 AC: 280 AN: 4830

European-Finnish (FIN) AF: 0.162 AC: 1719 AN: 10598

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9616 AN: 68016

Other (OTH) AF: 0.124 AC: 263 AN: 2114

Alfa AF: 0.122 Hom.: 265

Bravo AF: 0.0999

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.067
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
PromoterAI		-0.036	Neutral
gMVP		0.33
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs75638145;

hg19: chr15-31453147;