9-70536068-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_001366145.2(TRPM3):c.5045G>A(p.Arg1682Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,613,982 control chromosomes in the GnomAD database, including 261,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (26643 hom., cov: 32)
  • Exomes 𝑓: 0.56 (235232 hom.)
• Consequence: TRPM3 NM_001366145.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.57

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]

KLF9-DT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRPM3
• BP4: Computational evidence support a benign effect (MetaRNN=1.2846781E-6).
• BP6: Variant 9-70536068-C-T is Benign according to our data. Variant chr9-70536068-C-T is described in ClinVar as [Benign]. Clinvar id is 1232067.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM3	NM_001366145.2	c.5045G>A	p.Arg1682Gln	missense_variant	26/26	ENST00000677713.2
KLF9-DT	XR_001746707.3	n.467-14211C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM3	ENST00000677713.2	c.5045G>A	p.Arg1682Gln	missense_variant	26/26		NM_001366145.2	P4

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89386 AN: 151986 Hom.: 26625 Cov.: 32

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.584

GnomAD3 exomes AF: 0.580 AC: 145754 AN: 251452 Hom.: 43461 AF XY: 0.569 AC XY: 77325 AN XY: 135898

Gnomad AFR exome AF: 0.632

Gnomad AMR exome AF: 0.561

Gnomad ASJ exome AF: 0.563

Gnomad EAS exome AF: 0.841

Gnomad SAS exome AF: 0.405

Gnomad FIN exome AF: 0.655

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.573

GnomAD4 exome AF: 0.564 AC: 824096 AN: 1461878 Hom.: 235232 Cov.: 84 AF XY: 0.559 AC XY: 406702 AN XY: 727240

Gnomad4 AFR exome AF: 0.646

Gnomad4 AMR exome AF: 0.565

Gnomad4 ASJ exome AF: 0.569

Gnomad4 EAS exome AF: 0.798

Gnomad4 SAS exome AF: 0.409

Gnomad4 FIN exome AF: 0.656

Gnomad4 NFE exome AF: 0.560

Gnomad4 OTH exome AF: 0.566

GnomAD4 genome AF: 0.588 AC: 89440 AN: 152104 Hom.: 26643 Cov.: 32 AF XY: 0.590 AC XY: 43868 AN XY: 74376

Gnomad4 AFR AF: 0.630

Gnomad4 AMR AF: 0.557

Gnomad4 ASJ AF: 0.573

Gnomad4 EAS AF: 0.821

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.557

Gnomad4 OTH AF: 0.585

Alfa AF: 0.572 Hom.: 47564

Bravo AF: 0.593

TwinsUK AF: 0.561 AC: 2082

ALSPAC AF: 0.565 AC: 2177

ESP6500AA AF: 0.621 AC: 2735

ESP6500EA AF: 0.551 AC: 4741

ExAC AF: 0.579 AC: 70238

Asia WGS AF: 0.580 AC: 2017 AN: 3478

EpiCase AF: 0.565

EpiControl AF: 0.568

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.59
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;.;.
MetaRNN	Benign	0.0000013	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.00030	P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.88	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.045	D;T;T;T;T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;P;D;.;.;D;D
Vest4		0.46
MPC		0.58
ClinPred		0.020	T
GERP RS		5.8
gMVP		0.50

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

Other links and lift over

dbSNP: rs6560142; hg19: chr9-73150984; COSMIC: COSV62582299;