rs4929982

Positions:

• chr11-2414726-C-A
• chr11-2414726-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014555.4(TRPM5):​c.1733G>T​(p.Arg578Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R578Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27202898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM5	NM_014555.4	c.1733G>T	p.Arg578Leu	missense_variant	16/29	ENST00000696290.1	NP_055370.1
TRPM5	XM_017017628.2	c.1787G>T	p.Arg596Leu	missense_variant	13/26		XP_016873117.1
TRPM5	XM_047426858.1	c.1787G>T	p.Arg596Leu	missense_variant	13/26		XP_047282814.1
TRPM5	XM_047426859.1	c.584G>T	p.Arg195Leu	missense_variant	4/17		XP_047282815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM5	ENST00000696290.1	c.1733G>T	p.Arg578Leu	missense_variant	16/29		NM_014555.4	ENSP00000512529.1
TRPM5	ENST00000533060.5	c.1733G>T	p.Arg578Leu	missense_variant	11/24	1		ENSP00000434121.1
TRPM5	ENST00000528453.1	c.1733G>T	p.Arg578Leu	missense_variant	11/24	1		ENSP00000436809.1
TRPM5	ENST00000533881.5	c.1715G>T	p.Arg572Leu	missense_variant	11/24	1		ENSP00000434383.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1385774 Hom.: 0 Cov.: 67 AF XY: 0.00 AC XY: 0 AN XY: 682442

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.00032	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;D;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.41	T;T;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.63	.;N;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	N;N;D;N
REVEL	Benign	0.26
Sift	Benign	0.12	T;T;T;T
Sift4G	Uncertain	0.054	T;T;T;T
Polyphen		0.072, 0.032	.;B;B;.
Vest4		0.30, 0.30
MutPred		0.32		.;Loss of disorder (P = 0.0371);Loss of disorder (P = 0.0371);Loss of disorder (P = 0.0371);
MVP		0.30
MPC		0.13
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.24
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: rs4929982; hg19: chr11-2435956;