chr11-2405029-C-T

Position:

• chr11-2405029-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014555.4(TRPM5):​c.3406G>A​(p.Gly1136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,612,590 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (39 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (45 hom.)
• Consequence: TRPM5 NM_014555.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.357

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025331378).
• BP6: Variant 11-2405029-C-T is Benign according to our data. Variant chr11-2405029-C-T is described in ClinVar as [Benign]. Clinvar id is 786185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1989/152372) while in subpopulation AFR AF= 0.0446 (1853/41590). AF 95% confidence interval is 0.0429. There are 39 homozygotes in gnomad4. There are 925 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM5	NM_014555.4	c.3406G>A	p.Gly1136Ser	missense_variant	29/29	ENST00000696290.1
TRPM5	XM_047426858.1	c.3463G>A	p.Gly1155Ser	missense_variant	26/26
TRPM5	XM_047426859.1	c.2284G>A	p.Gly762Ser	missense_variant	17/17
TRPM5	XM_017017628.2	c.3470-322G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM5	ENST00000696290.1	c.3406G>A	p.Gly1136Ser	missense_variant	29/29		NM_014555.4	P2
	ENST00000433035.1	n.319+196C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1983 AN: 152254 Hom.: 39 Cov.: 34

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00314 AC: 778 AN: 247578 Hom.: 13 AF XY: 0.00233 AC XY: 313 AN XY: 134586

Gnomad AFR exome AF: 0.0417

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000995

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00135 AC: 1970 AN: 1460218 Hom.: 45 Cov.: 31 AF XY: 0.00116 AC XY: 845 AN XY: 726438

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000881

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.0131 AC: 1989 AN: 152372 Hom.: 39 Cov.: 34 AF XY: 0.0124 AC XY: 925 AN XY: 74506

Gnomad4 AFR AF: 0.0446

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00404 Hom.: 7

Bravo AF: 0.0153

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00387 AC: 469

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.9
DANN	Benign	0.64
DEOGEN2	Benign	0.078	.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.54	T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.43	N;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.25	T;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.059, 0.10	.;B;B;.
Vest4		0.047, 0.15, 0.13
MVP		0.030
MPC		0.088
ClinPred		0.014	T
GERP RS		0.35
Varity_R		0.054
gMVP		0.12

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: rs79526258; hg19: chr11-2426259;