chr9-70536194-G-A

Position:

chr9-70536194-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001366145.2(TRPM3):c.4919C>T(p.Thr1640Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,614,230 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.011 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 31 hom. )

Consequence

TRPM3
NM_001366145.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 5.29

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 -12 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=0.002388537).

BP6

Variant 9-70536194-G-A is Benign according to our data. Variant chr9-70536194-G-A is described in ClinVar as [Benign]. Clinvar id is 3039489.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1685/152340) while in subpopulation AFR AF= 0.0384 (1596/41576). AF 95% confidence interval is 0.0368. There are 33 homozygotes in gnomad4. There are 832 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1685 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM3	NM_001366145.2 linkuse as main transcript	c.4919C>T	p.Thr1640Ile	missense_variant	26/26	ENST00000677713.2	NP_001353074.1
KLF9-DT	XR_001746707.3 linkuse as main transcript	n.467-14085G>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.4919C>T	p.Thr1640Ile	missense_variant	26/26		NM_001366145.2	ENSP00000503830	P4	Q9HCF6-3

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1683

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0385

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00278

AC:

698

AN:

251470

Hom.:

AF XY:

0.00191

AC XY:

259

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0381

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00108

AC:

1584

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000924

AC XY:

672

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0381

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.00248

GnomAD4 genome

AF:

0.0111

AC:

1685

AN:

152340

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

832

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0384

Gnomad4 AMR

AF:

0.00470

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.0128

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0384

AC:

169

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00348

AC:

423

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TRPM3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.075

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

Eigen

Benign

-0.19

Eigen_PC

Benign

0.018

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;.;.

MetaRNN

Benign

0.0024

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

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.54

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

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

REVEL

Benign

0.028

Sift

Benign

0.080

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

Sift4G

Benign

0.48

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

Polyphen

0.062

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

Vest4

0.12

MVP

0.55

MPC

0.16

ClinPred

0.013

GERP RS

4.9

gMVP

0.27

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