9-70536471-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001366145.2(TRPM3):c.4642G>A(p.Gly1548Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,614,106 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (22 hom.)
• Consequence: TRPM3 NM_001366145.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.36

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRPM3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0073593557).
• BP6: Variant 9-70536471-C-T is Benign according to our data. Variant chr9-70536471-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3039881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM3	NM_001366145.2	c.4642G>A	p.Gly1548Arg	missense_variant	26/26	ENST00000677713.2
KLF9-DT	XR_001746707.3	n.467-13808C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM3	ENST00000677713.2	c.4642G>A	p.Gly1548Arg	missense_variant	26/26		NM_001366145.2	P4

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152096 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00322 AC: 809 AN: 251484 Hom.: 10 AF XY: 0.00327 AC XY: 445 AN XY: 135912

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.00323

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00292 AC: 4268 AN: 1461890 Hom.: 22 Cov.: 82 AF XY: 0.00284 AC XY: 2062 AN XY: 727246

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00263 AC: 401 AN: 152216 Hom.: 4 Cov.: 32 AF XY: 0.00280 AC XY: 208 AN XY: 74414

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.00304

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00191 Hom.: 1

Bravo AF: 0.00116

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00348 AC: 423

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TRPM3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

TRPM3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;.;.
MetaRNN	Benign	0.0074	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.;D;D
Vest4		0.70
MutPred		0.57		.;.;.;Gain of sheet (P = 0.0028);.;.;.;.;.;
MVP		0.55
MPC		0.60
ClinPred		0.038	T
GERP RS		5.7
gMVP		0.74

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: rs148192709; hg19: chr9-73151387;