chr19-49157855-G-A

Variant names:

• chr19-49157855-G-A
• rs3760663
• NM_017636.4:c.-12G>A

Variant summary

Our verdict is Benign. The variant received -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
• 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: Labcorp Genetics (formerly Invitae), G2P, 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 -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 VariationId is 260834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017636.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	NM_017636.4	MANE Select	c.-12G>A		5_prime_UTR	Exon 1 of 25	NP_060106.2
	TRPM4	NM_001321281.2		c.-12G>A		5_prime_UTR	Exon 1 of 23	NP_001308210.1
	TRPM4	NM_001195227.2		c.-12G>A		5_prime_UTR	Exon 1 of 24	NP_001182156.1	Q8TD43-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.-12G>A		5_prime_UTR	Exon 1 of 25	ENSP00000252826.4	Q8TD43-1
	TRPM4	ENST00000427978.6	TSL:1	c.-12G>A		5_prime_UTR	Exon 1 of 24	ENSP00000407492.1	Q8TD43-3
	TRPM4	ENST00000595519.5	TSL:1	n.-12G>A		non_coding_transcript_exon	Exon 1 of 23	ENSP00000469893.1	M0QYK7

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	not provided (1)
-	-	1	Progressive familial heart block type IB (1)

Computational scores

Source: dbNSFP v4.9

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;