chr16-19035776-C-A

Variant names:

• chr16-19035776-C-A
• rs769754817
• NM_024847.4:c.958C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024847.4(TMC7):​c.958C>A​(p.Arg320Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,624 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. 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. R320C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMC7 NM_024847.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13620627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC7	NM_024847.4	c.958C>A	p.Arg320Ser	missense_variant	Exon 7 of 16	ENST00000304381.10	NP_079123.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC7	ENST00000304381.10	c.958C>A	p.Arg320Ser	missense_variant	Exon 7 of 16	1	NM_024847.4	ENSP00000304710.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458624 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725460

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 85780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110284

Other (OTH) AF: 0.00 AC: 0 AN: 60274

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0019	.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.66	.;N;.
PhyloP100		3.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.070	N;N;N
REVEL	Benign	0.054
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.42
MutPred		0.43		Loss of MoRF binding (P = 0.0569);Loss of MoRF binding (P = 0.0569);.;
MVP		0.22
MPC		0.29
ClinPred		0.45	T
GERP RS		4.3
Varity_R		0.21
gMVP		0.24
Mutation Taster		=81/19	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: rs769754817; hg19: chr16-19047098; COSMIC: COSV100432674;