NM_144686.4:c.1987T>C

Variant names:

• chr19-54160532-A-G
• rs775857830
• NM_144686.4:c.1987T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144686.4(TMC4):​c.1987T>C​(p.Tyr663His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y663N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.55
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1987T>C	p.Tyr663His	missense_variant	Exon 14 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.2005T>C	p.Tyr669His	missense_variant	Exon 14 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.1525T>C	p.Tyr509His	missense_variant	Exon 11 of 12		XP_011524788.1
TMC4	XR_935741.3	n.2113T>C		non_coding_transcript_exon_variant	Exon 14 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.1987T>C	p.Tyr663His	missense_variant	Exon 14 of 15	1	NM_144686.4	ENSP00000479458.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248894 AF XY: 0.00000742

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: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461866 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	0.38	D
PhyloP100		4.6
PrimateAI	Uncertain	0.68	T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.47
MutPred		0.64		.;Loss of stability (P = 0.0595);
MVP		0.30
ClinPred		0.91	D
GERP RS		4.4
gMVP		0.83
Mutation Taster		=85/15	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: rs775857830; hg19: chr19-54664269;