chr16-19016563-T-C

Variant names:

• chr16-19016563-T-C
• rs375541654
• NM_024847.4:c.425T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024847.4(TMC7):​c.425T>C​(p.Leu142Pro) 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. 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. L142Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC7 NM_024847.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC7	NM_024847.4	c.425T>C	p.Leu142Pro	missense_variant	Exon 3 of 16	ENST00000304381.10	NP_079123.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC7	ENST00000304381.10	c.425T>C	p.Leu142Pro	missense_variant	Exon 3 of 16	1	NM_024847.4	ENSP00000304710.5
TMC7	ENST00000421369.3	c.95T>C	p.Leu32Pro	missense_variant	Exon 3 of 16	1		ENSP00000397081.3
TMC7	ENST00000569532.5	c.425T>C	p.Leu142Pro	missense_variant	Exon 3 of 15	2		ENSP00000455041.1
TMC7	ENST00000568469.5	n.466T>C		non_coding_transcript_exon_variant	Exon 3 of 10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.1	.;M;.
PhyloP100		5.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.94
MutPred		0.82		Gain of disorder (P = 0.0142);Gain of disorder (P = 0.0142);.;
MVP		0.60
MPC		1.2
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.95

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: rs375541654; hg19: chr16-19027885;