rs112014947

Variant names:

• chr19-54162758-C-G
• rs112014947
• NM_144686.4:c.1417G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-54162758-C-G
• chr19-54162758-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144686.4(TMC4):​c.1417G>C​(p.Val473Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. 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. V473I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14312652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1417G>C	p.Val473Leu	missense_variant	Exon 10 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1435G>C	p.Val479Leu	missense_variant	Exon 10 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.955G>C	p.Val319Leu	missense_variant	Exon 7 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1478G>C		non_coding_transcript_exon_variant	Exon 10 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.1417G>C	p.Val473Leu	missense_variant	Exon 10 of 15	1	NM_144686.4	ENSP00000479458.1
TMC4	ENST00000617472.4	c.1435G>C	p.Val479Leu	missense_variant	Exon 10 of 15	1		ENSP00000477627.1
TMC4	ENST00000613723.4	n.658G>C		non_coding_transcript_exon_variant	Exon 4 of 9	1
TMC4	ENST00000495398.1	n.248G>C		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.83
DEOGEN2	Benign	0.0028	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.33	T
Sift4G	Benign	1.0	T;T
Vest4		0.30
MutPred		0.33		.;Gain of helix (P = 0.132);
MVP		0.040
ClinPred		0.73	D
GERP RS		-0.99
gMVP		0.40

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: rs112014947; hg19: chr19-54666491; COSMIC: COSV55826668; COSMIC: COSV55826668;