chr11-2406677-G-A

Position:

• chr11-2406677-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014555.4(TRPM5):​c.3235C>T​(p.Arg1079Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,611,686 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.585

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.124749124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM5	NM_014555.4	c.3235C>T	p.Arg1079Trp	missense_variant	26/29	ENST00000696290.1
TRPM5	XM_017017628.2	c.3289C>T	p.Arg1097Trp	missense_variant	23/26
TRPM5	XM_047426858.1	c.3289C>T	p.Arg1097Trp	missense_variant	23/26
TRPM5	XM_047426859.1	c.2086C>T	p.Arg696Trp	missense_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM5	ENST00000696290.1	c.3235C>T	p.Arg1079Trp	missense_variant	26/29		NM_014555.4	P2
	ENST00000433035.1	n.320-1147G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000313 AC: 78 AN: 249358 Hom.: 0 AF XY: 0.000237 AC XY: 32 AN XY: 134836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1459328 Hom.: 1 Cov.: 32 AF XY: 0.000129 AC XY: 94 AN XY: 725902

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74508

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.3235C>T (p.R1079W) alteration is located in exon 21 (coding exon 21) of the TRPM5 gene. This alteration results from a C to T substitution at nucleotide position 3235, causing the arginine (R) at amino acid position 1079 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;D;.;.
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.0	.;M;.;.
MutationTaster	Benign	0.51	N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.46, 0.46, 0.47
MVP		0.33
MPC		0.45
ClinPred		0.29	T
GERP RS		1.5
Varity_R		0.38
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202069779; hg19: chr11-2427907;