Genetic Variant TMC7:p.Pro14Ser (chr16-18984103-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_024847.4(TMC7):c.40C>T(p.Pro14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000965 in 1,503,204 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. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

TMC7
NM_024847.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.046091586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC7	NM_024847.4 link	c.40C>T	p.Pro14Ser	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>T	p.Pro14Ser	missense_variant	Exon 1 of 16	1	NM_024847.4	ENSP00000304710.5	Q7Z402-1
TMC7	ENST00000569532.5 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 1 of 15	2		ENSP00000455041.1	H3BNW8
TMC7	ENST00000568469.5 link	n.81C>T		non_coding_transcript_exon_variant	Exon 1 of 10	2
TMC7	ENST00000421369.3 link	c.-742C>T		upstream_gene_variant		1		ENSP00000397081.3	Q7Z402-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000499

AC:

AN:

100222

AF XY:

0.0000536

show subpopulations

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:

0.000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000102

AC:

138

AN:

1351070

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

666318

show subpopulations

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:

0.00

AC:

AN:

75694

European-Finnish (FIN)

AF:

0.0000902

AC:

AN:

33254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3968

European-Non Finnish (NFE)

AF:

0.000125

AC:

133

AN:

1066076

Other (OTH)

AF:

0.0000355

AC:

AN:

56306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.40C>T (p.P14S) alteration is located in exon 1 (coding exon 1) of the TMC7 gene. This alteration results from a C to T substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by a serine (S). 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

0.078

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0023

.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

.;N

PhyloP100

0.52

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.57

N;N

REVEL

Benign

0.057

Sift

Benign

0.35

T;T

Sift4G

Benign

0.57

T;T

Polyphen

0.0

.;B

Vest4

0.074

MutPred

0.18

Gain of phosphorylation at P14 (P = 0.0052);Gain of phosphorylation at P14 (P = 0.0052);

MVP

0.24

MPC

0.26

ClinPred

0.038

GERP RS

2.3

PromoterAI

-0.39

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.021

gMVP

0.30

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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16-18984103-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over