chr11-2415234-C-T

Position:

• chr11-2415234-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014555.4(TRPM5):​c.1366G>A​(p.Ala456Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 1,572,974 control chromosomes in the GnomAD database, including 875 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (70 hom., cov: 34)
  • Exomes 𝑓: 0.031 (805 hom.)
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42

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=0.002408743).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0228 (3478/152324) while in subpopulation NFE AF= 0.0351 (2386/68002). AF 95% confidence interval is 0.0339. There are 70 homozygotes in gnomad4. There are 1624 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM5	NM_014555.4	c.1366G>A	p.Ala456Thr	missense_variant	14/29	ENST00000696290.1	NP_055370.1
TRPM5	XM_017017628.2	c.1420G>A	p.Ala474Thr	missense_variant	11/26		XP_016873117.1
TRPM5	XM_047426858.1	c.1420G>A	p.Ala474Thr	missense_variant	11/26		XP_047282814.1
TRPM5	XM_047426859.1	c.217G>A	p.Ala73Thr	missense_variant	2/17		XP_047282815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM5	ENST00000696290.1	c.1366G>A	p.Ala456Thr	missense_variant	14/29		NM_014555.4	ENSP00000512529.1
TRPM5	ENST00000533060.5	c.1366G>A	p.Ala456Thr	missense_variant	9/24	1		ENSP00000434121.1
TRPM5	ENST00000528453.1	c.1366G>A	p.Ala456Thr	missense_variant	9/24	1		ENSP00000436809.1
TRPM5	ENST00000533881.5	c.1348G>A	p.Ala450Thr	missense_variant	9/24	1		ENSP00000434383.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3480 AN: 152206 Hom.: 70 Cov.: 34

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0234 AC: 4137 AN: 176620 Hom.: 73 AF XY: 0.0238 AC XY: 2314 AN XY: 97408

Gnomad AFR exome AF: 0.00543

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.00473

Gnomad EAS exome AF: 0.0000732

Gnomad SAS exome AF: 0.00346

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0308 AC: 43688 AN: 1420650 Hom.: 805 Cov.: 37 AF XY: 0.0301 AC XY: 21183 AN XY: 704148

Gnomad4 AFR exome AF: 0.00522

Gnomad4 AMR exome AF: 0.0202

Gnomad4 ASJ exome AF: 0.00518

Gnomad4 EAS exome AF: 0.0000530

Gnomad4 SAS exome AF: 0.00354

Gnomad4 FIN exome AF: 0.0364

Gnomad4 NFE exome AF: 0.0357

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0228 AC: 3478 AN: 152324 Hom.: 70 Cov.: 34 AF XY: 0.0218 AC XY: 1624 AN XY: 74496

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0361

Gnomad4 NFE AF: 0.0351

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0282 Hom.: 36

Bravo AF: 0.0215

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0311 AC: 120

ESP6500AA AF: 0.00820 AC: 35

ESP6500EA AF: 0.0324 AC: 273

ExAC AF: 0.0200 AC: 2346

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0050
DANN	Benign	0.76
DEOGEN2	Benign	0.092	.;T;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.23	T;T;T;T
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.57	T;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0080, 0.0050	.;B;B;.
Vest4		0.030, 0.021, 0.033
MPC		0.086
ClinPred		0.0031	T
GERP RS		-6.4
Varity_R		0.034
gMVP		0.15

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: rs34551253; hg19: chr11-2436464; COSMIC: COSV50209748;