Variant chr16-18984074-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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. 15/21 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62

Variant links:

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]

TMC7 links:

TMC7 (HGNC:):

TMC7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC7	NM_024847.4 linkuse as main transcript	c.11C>A	p.Ser4Tyr	missense_variant	1/16	ENST00000304381.10	NP_079123.3	Q7Z402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMC7	ENST00000304381.10 linkuse as main transcript	c.11C>A	p.Ser4Tyr	missense_variant	1/16	1	NM_024847.4	ENSP00000304710.5	Q7Z402-1
TMC7	ENST00000569532.5 linkuse as main transcript	c.11C>A	p.Ser4Tyr	missense_variant	1/15	2		ENSP00000455041.1	H3BNW8
TMC7	ENST00000568469.5 linkuse as main transcript	n.52C>A		non_coding_transcript_exon_variant	1/10	2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000497

AC:

AN:

96672

Hom.:

AF XY:

0.000424

AC XY:

AN XY:

54234

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

664184

show subpopulations

Gnomad4 AFR exome

AF:

0.000146

Gnomad4 AMR exome

AF:

0.000728

Gnomad4 ASJ exome

AF:

0.00260

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000507

Gnomad4 OTH exome

AF:

0.000303

GnomAD4 genome

AF:

0.000105

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000516

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.000399

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

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

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.0040

.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.90

.;L

PrimateAI

Uncertain

0.62

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

GERP RS

1.9

Varity_R

0.028

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over