Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 9.99

Publications

16 publications found

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 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

TRPM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 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).

BP6

Variant 15-31067145-G-A is Benign according to our data. Variant chr15-31067145-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94063.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM1	NM_001252024.2	MANE Select	c.536C>T	p.Ser179Phe	missense	Exon 6 of 28	NP_001238953.1
TRPM1	NM_001252020.2		c.587C>T	p.Ser196Phe	missense	Exon 5 of 27	NP_001238949.1
TRPM1	NM_002420.6		c.470C>T	p.Ser157Phe	missense	Exon 5 of 27	NP_002411.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM1	ENST00000256552.11	TSL:1 MANE Select	c.536C>T	p.Ser179Phe	missense	Exon 6 of 28	ENSP00000256552.7
TRPM1	ENST00000558445.6	TSL:1	c.587C>T	p.Ser196Phe	missense	Exon 5 of 27	ENSP00000452946.2
TRPM1	ENST00000397795.7	TSL:1	c.470C>T	p.Ser157Phe	missense	Exon 5 of 27	ENSP00000380897.2

Frequencies

GnomAD3 genomes

AF:

0.00382

AC:

581

AN:

152128

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00323

AC:

806

AN:

249574

AF XY:

0.00316

show subpopulations

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 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.:

Cov.:

AF XY:

0.00436

AC XY:

3174

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000806

AC:

AN:

33480

American (AMR)

AF:

0.00183

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00462

AC:

247

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00520

AC:

5779

AN:

1112006

Other (OTH)

AF:

0.00328

AC:

198

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

390

780

1169

1559

1949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00382

AC:

581

AN:

152246

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41534

American (AMR)

AF:

0.00412

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00616

AC:

419

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00489

Hom.:

Bravo

AF:

0.00329

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00105

AC:

ESP6500EA

AF:

0.00316

AC:

ExAC

AF:

0.00319

AC:

385

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00421

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Congenital stationary night blindness 1C (2)

Retinitis pigmentosa (1)

TRPM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.0

PhyloP100

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.51

Sift

Uncertain

0.011

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.91

MVP

0.47

MPC

0.84

ClinPred

0.057

GERP RS

6.1

Varity_R

0.63

gMVP

0.57

Mutation Taster

=42/58

disease causing

(source)

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

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rs138886378

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over