NM_144686.4:c.1791C>T

Variant names:

• chr19-54161156-G-A
• rs765431768
• NM_144686.4:c.1791C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_144686.4(TMC4):​c.1791C>T​(p.Ser597Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,436,446 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMC4 NM_144686.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.15
• Publications: 0 publications found

Genes affected

TMC4 (HGNC:22998): (transmembrane channel like 4) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-4.15 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1791C>T	p.Ser597Ser	synonymous_variant	Exon 12 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1809C>T	p.Ser603Ser	synonymous_variant	Exon 12 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.1329C>T	p.Ser443Ser	synonymous_variant	Exon 9 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1852C>T		non_coding_transcript_exon_variant	Exon 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.1791C>T	p.Ser597Ser	synonymous_variant	Exon 12 of 15	1	NM_144686.4	ENSP00000479458.1
TMC4	ENST00000617472.4	c.1809C>T	p.Ser603Ser	synonymous_variant	Exon 12 of 15	1		ENSP00000477627.1
TMC4	ENST00000613723.4	n.1032C>T		non_coding_transcript_exon_variant	Exon 6 of 9	1
TMC4	ENST00000615945.4	n.-184C>T		upstream_gene_variant		2		ENSP00000481392.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000444 AC: 1 AN: 225350 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1436446 Hom.: 0 Cov.: 39 AF XY: 0.00000280 AC XY: 2 AN XY: 713476

African (AFR) AF: 0.00 AC: 0 AN: 31840

American (AMR) AF: 0.00 AC: 0 AN: 38066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 83340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5636

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101416

Other (OTH) AF: 0.0000169 AC: 1 AN: 59120

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.20
DANN	Benign	0.92
PhyloP100		-4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs765431768; hg19: chr19-54664893;