rs1796993

Variant names:

• chr9-72700522-G-A
• rs1796993
• NM_138691.3:c.241G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-72700522-G-A
• chr9-72700522-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_138691.3(TMC1):​c.241G>A​(p.Glu81Lys) variant causes a missense change. The variant allele was found at a frequency of 0.192 in 1,586,800 control chromosomes in the GnomAD database, including 32,970 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4128 hom., cov: 29)
  • Exomes 𝑓: 0.19 (28842 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.72
• Publications: 34 publications found

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]

TMC1 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.85843 (below the threshold of 3.09). Trascript score misZ: 1.5687 (below the threshold of 3.09). GenCC associations: The gene is linked to nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36, hearing loss, autosomal recessive, autosomal dominant nonsyndromic hearing loss.
• BP4: Computational evidence support a benign effect (MetaRNN=0.002365142).
• BP6: Variant 9-72700522-G-A is Benign according to our data. Variant chr9-72700522-G-A is described in ClinVar as Benign. ClinVar VariationId is 47869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138691.3. 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
	TMC1	NM_138691.3	MANE Select	c.241G>A	p.Glu81Lys	missense	Exon 8 of 24	NP_619636.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.241G>A	p.Glu81Lys	missense	Exon 8 of 24	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.241G>A	p.Glu81Lys	missense	Exon 6 of 22	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.241G>A	p.Glu81Lys	missense	Exon 7 of 23	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33917 AN: 151144 Hom.: 4116 Cov.: 29

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.241 AC: 59211 AN: 245954 AF XY: 0.238

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.343

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.387

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.188 AC: 269945 AN: 1435538 Hom.: 28842 Cov.: 28 AF XY: 0.191 AC XY: 136785 AN XY: 714872

African (AFR) AF: 0.270 AC: 8788 AN: 32490

American (AMR) AF: 0.329 AC: 14306 AN: 43436

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 6993 AN: 25398

East Asian (EAS) AF: 0.398 AC: 15382 AN: 38672

South Asian (SAS) AF: 0.311 AC: 26269 AN: 84400

European-Finnish (FIN) AF: 0.234 AC: 12114 AN: 51848

Middle Eastern (MID) AF: 0.202 AC: 1135 AN: 5626

European-Non Finnish (NFE) AF: 0.158 AC: 172758 AN: 1094748

Other (OTH) AF: 0.207 AC: 12200 AN: 58920

GnomAD4 genome AF: 0.224 AC: 33952 AN: 151262 Hom.: 4128 Cov.: 29 AF XY: 0.230 AC XY: 16986 AN XY: 73878

African (AFR) AF: 0.268 AC: 11050 AN: 41282

American (AMR) AF: 0.267 AC: 4067 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1023 AN: 3466

East Asian (EAS) AF: 0.385 AC: 1978 AN: 5142

South Asian (SAS) AF: 0.329 AC: 1583 AN: 4808

European-Finnish (FIN) AF: 0.228 AC: 2332 AN: 10242

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11258 AN: 67808

Other (OTH) AF: 0.218 AC: 459 AN: 2104

Alfa AF: 0.187 Hom.: 9943

Bravo AF: 0.225

TwinsUK AF: 0.160 AC: 595

ALSPAC AF: 0.154 AC: 592

ESP6500AA AF: 0.263 AC: 1157

ESP6500EA AF: 0.169 AC: 1449

ExAC AF: 0.238 AC: 28859

Asia WGS AF: 0.343 AC: 1189 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 36 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.010
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.81	L
PhyloP100		5.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.079
Sift	Benign	0.26	T
Sift4G	Benign	0.10	T
Polyphen		0.15	B
Vest4		0.10
MPC		0.19
ClinPred		0.015	T
GERP RS		5.5
Varity_R		0.32
gMVP		0.40
Mutation Taster		=96/4	polymorphism (auto)

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: rs1796993; hg19: chr9-75315438; COSMIC: COSV52781375;