16-19016593-T-C

Position:

• chr16-19016593-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024847.4(TMC7):​c.455T>C​(p.Ile152Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC7 NM_024847.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC7	NM_024847.4	c.455T>C	p.Ile152Thr	missense_variant	3/16	ENST00000304381.10	NP_079123.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC7	ENST00000304381.10	c.455T>C	p.Ile152Thr	missense_variant	3/16	1	NM_024847.4	ENSP00000304710.5
TMC7	ENST00000421369.3	c.125T>C	p.Ile42Thr	missense_variant	3/16	1		ENSP00000397081.3
TMC7	ENST00000569532.5	c.455T>C	p.Ile152Thr	missense_variant	3/15	2		ENSP00000455041.1
TMC7	ENST00000568469.5	n.496T>C		non_coding_transcript_exon_variant	3/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The c.455T>C (p.I152T) alteration is located in exon 3 (coding exon 3) of the TMC7 gene. This alteration results from a T to C substitution at nucleotide position 455, causing the isoleucine (I) at amino acid position 152 to be replaced by a threonine (T). 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	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.4	.;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.4	D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MutPred		0.64		Gain of disorder (P = 0.0108);Gain of disorder (P = 0.0108);.;
MVP		0.66
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.52
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-19027915;