rs397517839

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM4_SupportingPP3_ModerateBP6_Very_StrongBS1BS2

The NM_138691.3(TMC1):c.247_249delGAA(p.Glu83del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0119 in 1,588,288 control chromosomes in the GnomAD database, including 157 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 16 hom., cov: 29)

Exomes 𝑓: 0.012 ( 141 hom. )

Consequence

TMC1
NM_138691.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.69

Publications

5 publications found

Variant links:

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):

autosomal recessive nonsyndromic hearing loss 7
Inheritance: AD, Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
autosomal dominant nonsyndromic hearing loss 36
Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_138691.3. Strenght limited to Supporting due to length of the change: 1aa.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 9-72700517-GAGA-G is Benign according to our data. Variant chr9-72700517-GAGA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00958 (1451/151504) while in subpopulation NFE AF = 0.0139 (944/67854). AF 95% confidence interval is 0.0132. There are 16 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 SD,AR,AD gene

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.247_249delGAA	p.Glu83del	conservative_inframe_deletion	Exon 8 of 24	NP_619636.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMC1	ENST00000297784.10	TSL:1 MANE Select	c.247_249delGAA	p.Glu83del	conservative_inframe_deletion	Exon 8 of 24	ENSP00000297784.6	Q8TDI8
TMC1	ENST00000340019.4	TSL:5	c.247_249delGAA	p.Glu83del	conservative_inframe_deletion	Exon 6 of 22	ENSP00000341433.3	Q8TDI8
TMC1	ENST00000645208.2		c.247_249delGAA	p.Glu83del	conservative_inframe_deletion	Exon 7 of 23	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes

AF:

0.00960

AC:

1454

AN:

151392

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00245

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00646

Gnomad FIN

AF:

0.00475

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.0173

GnomAD2 exomes

AF:

0.0100

AC:

2464

AN:

245610

AF XY:

0.0107

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00723

Gnomad ASJ exome

AF:

0.00789

Gnomad EAS exome

AF:

0.0000555

Gnomad FIN exome

AF:

0.00534

Gnomad NFE exome

AF:

0.0157

Gnomad OTH exome

AF:

0.0180

GnomAD4 exome

AF:

0.0122

AC:

17463

AN:

1436784

Hom.:

141

AF XY:

0.0122

AC XY:

8701

AN XY:

715396

show subpopulations

African (AFR)

AF:

0.00282

AC:

AN:

32638

American (AMR)

AF:

0.00827

AC:

360

AN:

43508

Ashkenazi Jewish (ASJ)

AF:

0.00747

AC:

190

AN:

25424

East Asian (EAS)

AF:

0.0000774

AC:

AN:

38742

South Asian (SAS)

AF:

0.00416

AC:

352

AN:

84518

European-Finnish (FIN)

AF:

0.00585

AC:

302

AN:

51654

Middle Eastern (MID)

AF:

0.0550

AC:

309

AN:

5618

European-Non Finnish (NFE)

AF:

0.0139

AC:

15201

AN:

1095756

Other (OTH)

AF:

0.0111

AC:

654

AN:

58926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

685

1370

2056

2741

3426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

542

1084

1626

2168

2710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00958

AC:

1451

AN:

151504

Hom.:

Cov.:

AF XY:

0.00901

AC XY:

667

AN XY:

74050

show subpopulations

African (AFR)

AF:

0.00244

AC:

101

AN:

41374

American (AMR)

AF:

0.0116

AC:

177

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00646

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00475

AC:

AN:

10324

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0139

AC:

944

AN:

67854

Other (OTH)

AF:

0.0171

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

130

194

259

324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.0103

Asia WGS

AF:

0.00260

AC:

AN:

3474

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Hearing loss, autosomal recessive (1)

Nonsyndromic Hearing Loss, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.93

Position offset: 4

DS_AL_spliceai

0.96

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over