9-70536143-G-A

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.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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1657E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: TRPM3 NM_001366145.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.527

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=0.004575461).
• BP6: Variant 9-70536143-G-A is Benign according to our data. Variant chr9-70536143-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2659246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 177 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM3	ENST00000677713.2	c.4970C>T	p.Ala1657Val	missense_variant	26/26		NM_001366145.2	P4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152202 Hom.: 1 Cov.: 32

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.: 2 AF XY: 0.000971 AC XY: 132 AN XY: 135874

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.: 2 Cov.: 81 AF XY: 0.00133 AC XY: 966 AN XY: 727242

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.: 1 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74484

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.: 0

Bravo AF: 0.00109

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00196

ClinVar

Significance: Benign/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 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	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.73
Dann	Benign	0.30
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;.;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0046	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
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	T
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

Other links and lift over

dbSNP: rs148848073; hg19: chr9-73151059; COSMIC: COSV62584188;