rs34364959

Positions:

• chr11-2411436-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014555.4(TRPM5):​c.2698G>A​(p.Gly900Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 1,612,000 control chromosomes in the GnomAD database, including 6,331 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.077 (518 hom., cov: 33)
  • Exomes 𝑓: 0.086 (5813 hom.)
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122

Genes affected

TRPM5 (HGNC:14323): (transient receptor potential cation channel subfamily M member 5) This gene encodes a member of the transient receptor potential (TRP) protein family, which is a diverse group of proteins with structural features typical of ion channels. This protein plays an important role in taste transduction, and has characteristics of a calcium-activated, non-selective cation channel that carries Na+, K+, and Cs+ ions equally well, but not Ca(2+) ions. It is activated by lower concentrations of intracellular Ca(2+), and inhibited by higher concentrations. It is also a highly temperature-sensitive, heat activated channel showing a steep increase of inward currents at temperatures between 15 and 35 degrees Celsius. This gene is located within the Beckwith-Wiedemann syndrome critical region-1 on chromosome 11p15.5, and has been shown to be imprinted, with exclusive expression from the paternal allele. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012801886).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM5	NM_014555.4	c.2698G>A	p.Gly900Ser	missense_variant	23/29	ENST00000696290.1
TRPM5	XM_017017628.2	c.2752G>A	p.Gly918Ser	missense_variant	20/26
TRPM5	XM_047426858.1	c.2752G>A	p.Gly918Ser	missense_variant	20/26
TRPM5	XM_047426859.1	c.1549G>A	p.Gly517Ser	missense_variant	11/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM5	ENST00000696290.1	c.2698G>A	p.Gly900Ser	missense_variant	23/29		NM_014555.4	P2
TRPM5	ENST00000533060.5	c.2698G>A	p.Gly900Ser	missense_variant	18/24	1		A2
TRPM5	ENST00000528453.1	c.2698G>A	p.Gly900Ser	missense_variant	18/24	1		A2
TRPM5	ENST00000533881.5	c.2680G>A	p.Gly894Ser	missense_variant	18/24	1

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11682 AN: 152194 Hom.: 518 Cov.: 33

Gnomad AFR AF: 0.0457

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.0872

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0379

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0974

Gnomad OTH AF: 0.0989

GnomAD3 exomes AF: 0.0724 AC: 17989 AN: 248326 Hom.: 801 AF XY: 0.0738 AC XY: 9961 AN XY: 134954

Gnomad AFR exome AF: 0.0425

Gnomad AMR exome AF: 0.0558

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.0382

Gnomad SAS exome AF: 0.0175

Gnomad FIN exome AF: 0.0666

Gnomad NFE exome AF: 0.0979

Gnomad OTH exome AF: 0.0838

GnomAD4 exome AF: 0.0857 AC: 125159 AN: 1459688 Hom.: 5813 Cov.: 31 AF XY: 0.0839 AC XY: 60908 AN XY: 726036

Gnomad4 AFR exome AF: 0.0488

Gnomad4 AMR exome AF: 0.0603

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.0314

Gnomad4 SAS exome AF: 0.0188

Gnomad4 FIN exome AF: 0.0687

Gnomad4 NFE exome AF: 0.0949

Gnomad4 OTH exome AF: 0.0832

GnomAD4 genome AF: 0.0767 AC: 11687 AN: 152312 Hom.: 518 Cov.: 33 AF XY: 0.0767 AC XY: 5713 AN XY: 74470

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.0870

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0378

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.0757

Gnomad4 NFE AF: 0.0973

Gnomad4 OTH AF: 0.0979

Alfa AF: 0.0913 Hom.: 737

Bravo AF: 0.0776

TwinsUK AF: 0.0960 AC: 356

ALSPAC AF: 0.0963 AC: 371

ESP6500AA AF: 0.0486 AC: 214

ESP6500EA AF: 0.0941 AC: 808

ExAC AF: 0.0721 AC: 8729

Asia WGS AF: 0.0230 AC: 82 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.105

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.052
DANN	Benign	0.94
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.19	T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.77	N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.78	T;T;T;T
Sift4G	Benign	0.93	T;T;T;T
Polyphen		0.0010, 0.0040	.;B;B;.
Vest4		0.11, 0.082, 0.11
MPC		0.093
ClinPred		0.0078	T
GERP RS		-4.3
Varity_R		0.031
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34364959; hg19: chr11-2432666; COSMIC: COSV50150864; COSMIC: COSV50150864;