rs397517838

chr9-72826933-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_138691.3(TMC1):c.2068G>A(p.Ala690Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A690A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.20

Genes affected

TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Extracellular (size 43) in uniprot entity TMC1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_138691.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25842336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3	c.2068G>A	p.Ala690Thr	missense_variant	21/24	ENST00000297784.10
TMC1	XM_017014256.2	c.2071G>A	p.Ala691Thr	missense_variant	18/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.2068G>A	p.Ala690Thr	missense_variant	21/24	1	NM_138691.3	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 14, 2010

Variant classified as Uncertain Significance - Favor Benign. The Ala690Thr varia nt has not been reported in the literature nor previously identified by our labo ratory. This residue is conserved in mammals; however, it is not conserved in ch ickens and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a h igh likelihood of impact to the protein. However, this information is not very p redictive of pathogenicity. It should be noted that this lab has only sequenced the TMC1 in 104 individuals such that the full spectrum of benign variation has not yet been defined for this gene, increasing the possibility that this may be a benign variant. In summary, the clinical significance of this variant cannot b e determined with certainty at this time; however based upon the arguments descr ibed above, we would lean towards a more likely benign role. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.2068G>A (p.A690T) alteration is located in exon 21 (coding exon 17) of the TMC1 gene. This alteration results from a G to A substitution at nucleotide position 2068, causing the alanine (A) at amino acid position 690 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	Benign	0.16
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T;.;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L;L;.;L;.
MutationTaster	Benign	0.82	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.79	N;.;.;N;.
REVEL	Benign	0.090
Sift	Benign	0.20	T;.;.;T;.
Sift4G	Uncertain	0.0070	D;.;.;D;.
Polyphen		0.69	P;P;.;P;.
Vest4		0.46
MutPred		0.44		Loss of stability (P = 0.0388);Loss of stability (P = 0.0388);.;Loss of stability (P = 0.0388);.;
MVP		0.53
MPC		0.25
ClinPred		0.80	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs397517838; hg19: chr9-75441849;