9-70536194-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.011 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (31 hom.)
• Consequence: TRPM3 NM_001366145.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.29

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=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 criteria_provided_single_submitter, 1 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 GnomAd at 1683 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM3	NM_001366145.2	c.4919C>T	p.Thr1640Ile	missense_variant	26/26	ENST00000677713.2
KLF9-DT	XR_001746707.3	n.467-14085G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM3	ENST00000677713.2	c.4919C>T	p.Thr1640Ile	missense_variant	26/26		NM_001366145.2	P4

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1683 AN: 152222 Hom.: 33 Cov.: 32

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.: 11 AF XY: 0.00191 AC XY: 259 AN XY: 135900

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.: 31 Cov.: 82 AF XY: 0.000924 AC XY: 672 AN XY: 727244

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.: 33 Cov.: 32 AF XY: 0.0112 AC XY: 832 AN XY: 74496

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.: 10

Bravo AF: 0.0128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0384 AC: 169

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00348 AC: 423

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TRPM3-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Benign	0.95
Eigen	Benign	-0.19
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.97	D
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	T
MutationTaster	Benign	0.54	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
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	T
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

Other links and lift over

dbSNP: rs13440436; hg19: chr9-73151110;