rs886277

Positions:

• chr11-2418537-T-C

Variant summary

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

The NM_014555.4(TRPM5):​c.704A>G​(p.Asn235Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,609,256 control chromosomes in the GnomAD database, including 144,792 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (17434 hom., cov: 31)
  • Exomes 𝑓: 0.41 (127358 hom.)
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.244

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=5.790589E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM5	NM_014555.4	c.704A>G	p.Asn235Ser	missense_variant	10/29	ENST00000696290.1	NP_055370.1
TRPM5	XM_017017628.2	c.758A>G	p.Asn253Ser	missense_variant	7/26		XP_016873117.1
TRPM5	XM_047426858.1	c.758A>G	p.Asn253Ser	missense_variant	7/26		XP_047282814.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM5	ENST00000696290.1	c.704A>G	p.Asn235Ser	missense_variant	10/29		NM_014555.4	ENSP00000512529	P2
TRPM5	ENST00000533060.5	c.704A>G	p.Asn235Ser	missense_variant	5/24	1		ENSP00000434121	A2
TRPM5	ENST00000528453.1	c.704A>G	p.Asn235Ser	missense_variant	5/24	1		ENSP00000436809	A2
TRPM5	ENST00000533881.5	c.686A>G	p.Asn229Ser	missense_variant	5/24	1		ENSP00000434383

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70824 AN: 151542 Hom.: 17408 Cov.: 31

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.438

GnomAD3 exomes AF: 0.443 AC: 107787 AN: 243486 Hom.: 24966 AF XY: 0.433 AC XY: 57223 AN XY: 132270

Gnomad AFR exome AF: 0.613

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.263

Gnomad EAS exome AF: 0.674

Gnomad SAS exome AF: 0.417

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.413 AC: 601553 AN: 1457596 Hom.: 127358 Cov.: 48 AF XY: 0.411 AC XY: 298119 AN XY: 724842

Gnomad4 AFR exome AF: 0.610

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.261

Gnomad4 EAS exome AF: 0.700

Gnomad4 SAS exome AF: 0.417

Gnomad4 FIN exome AF: 0.426

Gnomad4 NFE exome AF: 0.395

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.467 AC: 70893 AN: 151660 Hom.: 17434 Cov.: 31 AF XY: 0.464 AC XY: 34395 AN XY: 74086

Gnomad4 AFR AF: 0.606

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.394

Gnomad4 OTH AF: 0.439

Alfa AF: 0.403 Hom.: 25539

Bravo AF: 0.479

TwinsUK AF: 0.369 AC: 1368

ALSPAC AF: 0.396 AC: 1526

ESP6500AA AF: 0.613 AC: 2693

ESP6500EA AF: 0.385 AC: 3312

ExAC AF: 0.442 AC: 53329

Asia WGS AF: 0.540 AC: 1876 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.1
DANN	Benign	0.19
DEOGEN2	Benign	0.10	.;T;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.11	T;T;T;T
MetaRNN	Benign	0.0000058	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.67	.;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.44	N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.74	T;T;T;T
Sift4G	Benign	0.83	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.029, 0.013, 0.028
MPC		0.071
ClinPred		0.0029	T
GERP RS		1.4
Varity_R		0.038
gMVP		0.24

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: rs886277; hg19: chr11-2439767; COSMIC: COSV50148399;