dbSNP rs980844461: TMC7:p.Pro14Ala (chr16-18984103-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024847.4(TMC7):c.40C>G(p.Pro14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,351,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. P14L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TMC7
NM_024847.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.522

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06718385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC7	NM_024847.4 link	c.40C>G	p.Pro14Ala	missense_variant	Exon 1 of 16	ENST00000304381.10	NP_079123.3	Q7Z402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMC7	ENST00000304381.10 link	c.40C>G	p.Pro14Ala	missense_variant	Exon 1 of 16	1	NM_024847.4	ENSP00000304710.5	Q7Z402-1
TMC7	ENST00000569532.5 link	c.40C>G	p.Pro14Ala	missense_variant	Exon 1 of 15	2		ENSP00000455041.1	H3BNW8
TMC7	ENST00000568469.5 link	n.81C>G		non_coding_transcript_exon_variant	Exon 1 of 10	2
TMC7	ENST00000421369.3 link	c.-742C>G		upstream_gene_variant		1		ENSP00000397081.3	Q7Z402-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.40e-7

AC:

AN:

1351070

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

666318

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27562

American (AMR)

AF:

0.00

AC:

AN:

32300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24036

East Asian (EAS)

AF:

0.00

AC:

AN:

31874

South Asian (SAS)

AF:

0.0000132

AC:

AN:

75694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3968

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1066076

Other (OTH)

AF:

0.00

AC:

AN:

56306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0024

.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

.;N

PhyloP100

0.52

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.79

N;N

REVEL

Benign

0.065

Sift

Benign

0.12

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.018

.;B

Vest4

0.14

MutPred

0.13

Loss of glycosylation at P14 (P = 0.0202);Loss of glycosylation at P14 (P = 0.0202);

MVP

0.27

MPC

0.25

ClinPred

0.085

GERP RS

2.3

PromoterAI

-0.27

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.025

gMVP

0.23

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over