rs3784589

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBA1

The NM_001252024.2(TRPM1):c.4189G>T(p.Glu1397Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,614,030 control chromosomes in the GnomAD database, including 3,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1397E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.065 ( 368 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3152 hom. )

Consequence

TRPM1
NM_001252024.2 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.20

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.141 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

BP6

Variant 15-31002511-C-A is Benign according to our data. Variant chr15-31002511-C-A is described in ClinVar as [Benign]. Clinvar id is 315498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TRPM1	NM_001252024.2 linkuse as main transcript	c.4189G>T	p.Glu1397Ter	stop_gained	28/28	ENST00000256552.11
TRPM1	NM_001252020.2 linkuse as main transcript	c.4240G>T	p.Glu1414Ter	stop_gained	27/27
TRPM1	NM_002420.6 linkuse as main transcript	c.4123G>T	p.Glu1375Ter	stop_gained	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11 linkuse as main transcript	c.4189G>T	p.Glu1397Ter	stop_gained	28/28	1	NM_001252024.2	P4	Q7Z4N2-6
	ENST00000665655.1 linkuse as main transcript	n.71+10270C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0644

AC:

9799

AN:

152068

Hom.:

364

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0752

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.0462

Gnomad ASJ

AF:

0.0620

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.0768

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0585

Gnomad OTH

AF:

0.0679

GnomAD3 exomes

AF:

0.0632

AC:

15773

AN:

249512

Hom.:

681

AF XY:

0.0679

AC XY:

9195

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.0809

Gnomad AMR exome

AF:

0.0336

Gnomad ASJ exome

AF:

0.0696

Gnomad EAS exome

AF:

0.00912

Gnomad SAS exome

AF:

0.131

Gnomad FIN exome

AF:

0.0693

Gnomad NFE exome

AF:

0.0582

Gnomad OTH exome

AF:

0.0650

GnomAD4 exome

AF:

0.0599

AC:

87603

AN:

1461846

Hom.:

3152

Cov.:

AF XY:

0.0625

AC XY:

45449

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0770

Gnomad4 AMR exome

AF:

0.0354

Gnomad4 ASJ exome

AF:

0.0714

Gnomad4 EAS exome

AF:

0.0219

Gnomad4 SAS exome

AF:

0.131

Gnomad4 FIN exome

AF:

0.0660

Gnomad4 NFE exome

AF:

0.0554

Gnomad4 OTH exome

AF:

0.0618

GnomAD4 genome

AF:

0.0645

AC:

9820

AN:

152184

Hom.:

368

Cov.:

AF XY:

0.0660

AC XY:

4911

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0755

Gnomad4 AMR

AF:

0.0460

Gnomad4 ASJ

AF:

0.0620

Gnomad4 EAS

AF:

0.0159

Gnomad4 SAS

AF:

0.125

Gnomad4 FIN

AF:

0.0768

Gnomad4 NFE

AF:

0.0585

Gnomad4 OTH

AF:

0.0672

Alfa

AF:

0.0557

Hom.:

539

Bravo

AF:

0.0603

TwinsUK

AF:

0.0550

AC:

204

ALSPAC

AF:

0.0547

AC:

211

ESP6500AA

AF:

0.0793

AC:

293

ESP6500EA

AF:

0.0565

AC:

463

ExAC

AF:

0.0653

AC:

7888

Asia WGS

AF:

0.0680

AC:

235

AN:

3478

EpiCase

AF:

0.0590

EpiControl

AF:

0.0557

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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	Mar 06, 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. -

not provided

Benign:2

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	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

D;D;D;D

Vest4

0.58

GERP RS

5.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over