NM_017636.4:c.3405A>C

Variant names:

• chr19-49210786-A-C
• rs144647383
• NM_017636.4:c.3405A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017636.4(TRPM4):​c.3405A>C​(p.Ala1135Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,613,956 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (8 hom.)
• Consequence: TRPM4 NM_017636.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.86
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-49210786-A-C is Benign according to our data. Variant chr19-49210786-A-C is described in ClinVar as Benign. ClinVar VariationId is 241178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.86 with no splicing effect.
• BS2: High AC in GnomAd4 at 640 AD gene.

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.3405A>C	p.Ala1135Ala	synonymous	Exon 22 of 25	NP_060106.2
	TRPM4	NM_001321281.2		c.3060A>C	p.Ala1020Ala	synonymous	Exon 20 of 23	NP_001308210.1
	TRPM4	NM_001195227.2		c.2970A>C	p.Ala990Ala	synonymous	Exon 21 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.3405A>C	p.Ala1135Ala	synonymous	Exon 22 of 25	ENSP00000252826.4	Q8TD43-1
	TRPM4	ENST00000427978.6	TSL:1	c.2970A>C	p.Ala990Ala	synonymous	Exon 21 of 24	ENSP00000407492.1	Q8TD43-3
	TRPM4	ENST00000595519.5	TSL:1	n.*2815A>C		non_coding_transcript_exon	Exon 20 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 152172 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00108 AC: 270 AN: 249632 AF XY: 0.000711

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000422 AC: 617 AN: 1461666 Hom.: 8 Cov.: 34 AF XY: 0.000337 AC XY: 245 AN XY: 727098

African (AFR) AF: 0.0159 AC: 533 AN: 33478

American (AMR) AF: 0.000514 AC: 23 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111978

Other (OTH) AF: 0.000811 AC: 49 AN: 60388

GnomAD4 genome AF: 0.00420 AC: 640 AN: 152290 Hom.: 8 Cov.: 31 AF XY: 0.00403 AC XY: 300 AN XY: 74458

African (AFR) AF: 0.0147 AC: 612 AN: 41572

American (AMR) AF: 0.00157 AC: 24 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00513 Hom.: 5

Bravo AF: 0.00503

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Progressive familial heart block type IB (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.50
DANN	Benign	0.55
PhyloP100		-3.9
PromoterAI		0.14	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs144647383; hg19: chr19-49714043;