chr19-49157855-G-A

Variant names:

• chr19-49157855-G-A
• rs3760663
• ENST00000595519.5:n.-12G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000595519.5(TRPM4):​n.-12G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,534,342 control chromosomes in the GnomAD database, including 58,096 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (4098 hom., cov: 31)
  • Exomes 𝑓: 0.27 (53998 hom.)
• Consequence: TRPM4 ENST00000595519.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.08
• Publications: 15 publications found

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

TRPM4 Gene-Disease associations (from GenCC):

• erythrokeratodermia variabilis et progressiva 6

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive familial heart block type IB

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4	c.-12G>A		5_prime_UTR_variant	Exon 1 of 25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10	c.-12G>A		5_prime_UTR_variant	Exon 1 of 25	1	NM_017636.4	ENSP00000252826.4

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31620 AN: 151994 Hom.: 4098 Cov.: 31

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0523

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.237 AC: 32070 AN: 135490 AF XY: 0.247

Gnomad AFR exome AF: 0.0661

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.0587

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.273 AC: 376879 AN: 1382230 Hom.: 53998 Cov.: 35 AF XY: 0.275 AC XY: 187854 AN XY: 682050

African (AFR) AF: 0.0584 AC: 1842 AN: 31542

American (AMR) AF: 0.159 AC: 5675 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 7302 AN: 25132

East Asian (EAS) AF: 0.0484 AC: 1730 AN: 35732

South Asian (SAS) AF: 0.316 AC: 25038 AN: 79126

European-Finnish (FIN) AF: 0.275 AC: 9395 AN: 34122

Middle Eastern (MID) AF: 0.290 AC: 1432 AN: 4946

European-Non Finnish (NFE) AF: 0.287 AC: 309692 AN: 1078206

Other (OTH) AF: 0.256 AC: 14773 AN: 57770

GnomAD4 genome AF: 0.208 AC: 31609 AN: 152112 Hom.: 4098 Cov.: 31 AF XY: 0.208 AC XY: 15460 AN XY: 74344

African (AFR) AF: 0.0679 AC: 2821 AN: 41546

American (AMR) AF: 0.176 AC: 2695 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 959 AN: 3468

East Asian (EAS) AF: 0.0519 AC: 267 AN: 5148

South Asian (SAS) AF: 0.308 AC: 1484 AN: 4824

European-Finnish (FIN) AF: 0.264 AC: 2792 AN: 10578

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19797 AN: 67948

Other (OTH) AF: 0.230 AC: 485 AN: 2110

Alfa AF: 0.170 Hom.: 536

Bravo AF: 0.192

Asia WGS AF: 0.163 AC: 569 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 22, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive familial heart block type IB Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.3
DANN	Benign	0.95
PhyloP100		-1.1
PromoterAI		-0.0067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3760663; hg19: chr19-49661112;