9-70536143-G-A

Position:

chr9-70536143-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_001366145.2(TRPM3):c.4970C>T(p.Ala1657Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,206 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

TRPM3
NM_001366145.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.527

Variant links:

Genes affected

TRPM3 (HGNC:17992): (transient receptor potential cation channel subfamily M member 3) The product of this gene belongs to the family of transient receptor potential (TRP) channels. TRP channels are cation-selective channels important for cellular calcium signaling and homeostasis. The protein encoded by this gene mediates calcium entry, and this entry is potentiated by calcium store depletion. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

TRPM3 links:

KLF9-DT (HGNC:):

KLF9-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRPM3. . Gene score misZ 3.1768 (greater than the threshold 3.09). Trascript score misZ 3.8237 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, schizophrenia, autosomal dominant non-syndromic intellectual disability, cataract-glaucoma syndrome, neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, cataract 50 with or without glaucoma.

BP4

Computational evidence support a benign effect (MetaRNN=0.004575461).

BP6

Variant 9-70536143-G-A is Benign according to our data. Variant chr9-70536143-G-A is described in ClinVar as [Benign]. Clinvar id is 2659246.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 177 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM3	NM_001366145.2 linkuse as main transcript	c.4970C>T	p.Ala1657Val	missense_variant	26/26	ENST00000677713.2	NP_001353074.1
KLF9-DT	XR_001746707.3 linkuse as main transcript	n.467-14136G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM3	ENST00000677713.2 linkuse as main transcript	c.4970C>T	p.Ala1657Val	missense_variant	26/26		NM_001366145.2	ENSP00000503830	P4	Q9HCF6-3

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

177

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00203

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000994

AC:

250

AN:

251420

Hom.:

AF XY:

0.000971

AC XY:

132

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00143

AC:

2089

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

966

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00175

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00116

AC:

177

AN:

152320

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00203

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00109

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000947

AC:

115

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TRPM3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

TRPM3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.73

DANN

Benign

0.30

DEOGEN2

Benign

0.064

.;.;T;T;T;.;.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.82

T;T;T;T;T;T;T;.;.

M_CAP

Benign

0.010

MetaRNN

Benign

0.0046

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.56

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.51

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.25

T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;.;.;B;B

Vest4

0.019

MVP

0.15

MPC

0.11

ClinPred

0.0041

GERP RS

0.63

gMVP

0.26

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