16-19021694-G-C

Variant names:

• chr16-19021694-G-C
• rs775401914
• NM_024847.4:c.526G>C

Variant summary

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

The NM_001324263.1(TMC7):​c.-488G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMC7 NM_001324263.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• 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: 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=0.08401424).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324263.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC7	NM_024847.4	MANE Select	c.526G>C	p.Val176Leu	missense	Exon 4 of 16	NP_079123.3	Q7Z402-1
	TMC7	NM_001324263.1		c.-488G>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 16	NP_001311192.1
	TMC7	NM_001324268.1		c.-353G>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001311197.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC7	ENST00000304381.10	TSL:1 MANE Select	c.526G>C	p.Val176Leu	missense	Exon 4 of 16	ENSP00000304710.5	Q7Z402-1
	TMC7	ENST00000421369.3	TSL:1	c.196G>C	p.Val66Leu	missense	Exon 4 of 16	ENSP00000397081.3	Q7Z402-2
	TMC7	ENST00000569532.5	TSL:2	c.526G>C	p.Val176Leu	missense	Exon 4 of 15	ENSP00000455041.1	H3BNW8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.12
Sift	Benign	0.75	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.45		Loss of stability (P = 0.3533)
MVP		0.081
MPC		0.26
ClinPred		0.44	T
GERP RS		4.3
Varity_R		0.081
gMVP		0.48

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

Other links and lift over

dbSNP: rs775401914; hg19: chr16-19033016;