rs781173030

Variant names:

• chr16-18984074-C-A
• rs781173030
• NM_024847.4:c.11C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-18984074-C-A
• chr16-18984074-C-G
• chr16-18984074-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024847.4(TMC7):​c.11C>A​(p.Ser4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,498,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TMC7 NM_024847.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62
• Publications: 0 publications found

Genes affected

TMC7 (HGNC:23000): (transmembrane channel like 7) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004229039).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC7	NM_024847.4	c.11C>A	p.Ser4Tyr	missense_variant	Exon 1 of 16	ENST00000304381.10	NP_079123.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC7	ENST00000304381.10	c.11C>A	p.Ser4Tyr	missense_variant	Exon 1 of 16	1	NM_024847.4	ENSP00000304710.5
TMC7	ENST00000569532.5	c.11C>A	p.Ser4Tyr	missense_variant	Exon 1 of 15	2		ENSP00000455041.1
TMC7	ENST00000568469.5	n.52C>A		non_coding_transcript_exon_variant	Exon 1 of 10	2
TMC7	ENST00000421369.3	c.-771C>A		upstream_gene_variant		1		ENSP00000397081.3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000497 AC: 48 AN: 96672 AF XY: 0.000424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000657

Gnomad ASJ exome AF: 0.00346

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00242

GnomAD4 exome AF: 0.000119 AC: 160 AN: 1346742 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 72 AN XY: 664184

African (AFR) AF: 0.000146 AC: 4 AN: 27320

American (AMR) AF: 0.000728 AC: 23 AN: 31584

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 62 AN: 23876

East Asian (EAS) AF: 0.00 AC: 0 AN: 31306

South Asian (SAS) AF: 0.00 AC: 0 AN: 75284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3958

European-Non Finnish (NFE) AF: 0.0000507 AC: 54 AN: 1064150

Other (OTH) AF: 0.000303 AC: 17 AN: 56048

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74344

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000399 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>A (p.S4Y) alteration is located in exon 1 (coding exon 1) of the TMC7 gene. This alteration results from a C to A substitution at nucleotide position 11, causing the serine (S) at amino acid position 4 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.75
DEOGEN2	Benign	0.0040	.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.90	.;L
PhyloP100		1.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.14
Sift	Benign	0.17	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.21	.;B
Vest4		0.19
MutPred		0.15		Loss of glycosylation at S4 (P = 0.0853);Loss of glycosylation at S4 (P = 0.0853);
MVP		0.34
MPC		0.39
ClinPred		0.035	T
GERP RS		1.9
PromoterAI		0.061	Neutral
Varity_R		0.028
gMVP		0.38
Mutation Taster		=91/9	polymorphism

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: rs781173030; hg19: chr16-18995396;