chr19-49157855-G-A

Position:

• chr19-49157855-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017636.4(TRPM4):​c.-12G>A variant causes a 5 prime UTR 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4098 hom., cov: 31)
  • Exomes 𝑓: 0.27 (53998 hom.)
• Consequence: TRPM4 NM_017636.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.08

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-49157855-G-A is Benign according to our data. Variant chr19-49157855-G-A is described in ClinVar as [Benign]. Clinvar id is 260834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49157855-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TRPM4	NM_017636.4	c.-12G>A		5_prime_UTR_variant	1/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10	c.-12G>A		5_prime_UTR_variant	1/25	1	NM_017636.4	P1

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

GnomAD3 exomes AF: 0.237 AC: 32070 AN: 135490 Hom.: 4360 AF XY: 0.247 AC XY: 17942 AN XY: 72678

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 SAS exome AF: 0.306

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

Gnomad4 AFR exome AF: 0.0584

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.0484

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.287

Gnomad4 OTH exome AF: 0.256

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

Gnomad4 AFR AF: 0.0679

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.0519

Gnomad4 SAS AF: 0.308

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.230

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2016	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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Progressive familial heart block type IB Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs3760663; hg19: chr19-49661112;