9-72816213-A-G

Position:

chr9-72816213-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_138691.3(TMC1):c.1763+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00076 in 1,613,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00079 ( 0 hom. )

Consequence

TMC1
NM_138691.3 splice_region, intron

Scores

Splicing: ADA: 0.9991

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.04

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 links:

TMC1 (HGNC:):

TMC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-72816213-A-G is Pathogenic according to our data. Variant chr9-72816213-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 47864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72816213-A-G is described in Lovd as [Pathogenic]. Variant chr9-72816213-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC1	NM_138691.3 linkuse as main transcript	c.1763+3A>G		splice_region_variant, intron_variant		ENST00000297784.10	NP_619636.2	Q8TDI8
TMC1	XM_017014256.2 linkuse as main transcript	c.1766+3A>G		splice_region_variant, intron_variant			XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10 linkuse as main transcript	c.1763+3A>G		splice_region_variant, intron_variant		1	NM_138691.3	ENSP00000297784.6		Q8TDI8

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000613

AC:

154

AN:

251290

Hom.:

AF XY:

0.000663

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000786

AC:

1148

AN:

1461028

Hom.:

Cov.:

AF XY:

0.000755

AC XY:

549

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00146

Gnomad4 NFE exome

AF:

0.000921

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000512

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000630

Hom.:

Bravo

AF:

0.000438

EpiCase

AF:

0.000327

EpiControl

AF:

0.000711

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change falls in intron 19 of the TMC1 gene. It does not directly change the encoded amino acid sequence of the TMC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs370898981, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with autosomal recessive deafness (PMID: 21252500). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 47864). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site resulting in the addition of 47 nucleotides from the intron and a subsequent frameshift and introduces a premature termination codon (PMID: 21252500). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2022	Non-canonical splice site variant demonstrated to result in loss-of-function; aberrant splicing results in a 47 base pair extension of exon 19, causing a frameshift, leading to a premature stop codon in exon 20 and the incorporation of 81 aberrant amino acids in the protein (de Heer et al., 2011); This variant is associated with the following publications: (PMID: 31980526, 33352559, 24933710, 34758253, 23208854, 21252500, 31152317) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive nonsyndromic hearing loss 7

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The TMC1 c.1763+3A>G splice region variant was first reported by de Heer et al. (2011) in a homozygous state in three siblings from a large, distantly-consanguineous Dutch family affected with autosomal recessive nonsyndromic hearing loss. Both unaffected parents were heterozygous for this variant. The c.1763+3A>G variant was subsequently identified in a compound heterozygous state with a nonsense variant in a patient of European ethnicity (Schrauwen et al. 2013). The variant was found in a heterozygous state in one of 177 Dutch control individuals and is reported at a frequency of 0.00130 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR analysis on RNA isolated from blood of a homozygous patient revealed that the c.1763+3A>G variant causes alternative splicing and introduces 47 bp of intronic sequence into exon 19, which ultimately results in a frameshift and premature stop. Minigene analysis revealed that the variant completely abolished the normal splicing signal (de Heer et al. 2011). Based on the evidence, the p.1763+3A>G variant is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Jun 21, 2017	- -

Autosomal dominant nonsyndromic hearing loss 36

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 04, 2024

Variant summary: TMC1 c.1763+3A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (de Heer_2011). The variant allele was found at a frequency of 0.00061 in 251290 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TMC1 causing Nonsyndromic Hearing Loss And Deafness, Type 7 (0.00061 vs 0.0011), allowing no conclusion about variant significance. c.1763+3A>G has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 7 and this variant co-segregated with the disease (de Heer_2011, Kraatari-Tiri_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35407445, 21252500). ClinVar contains an entry for this variant (Variation ID: 47864). Based on the evidence outlined above, the variant was classified as pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 11, 2017

The c.1763+3A>G variant in TMC1 has been previously reported in the homozygous s tate in one individual and in the compound heterozygous state in five other indi viduals with hearing loss, and segregated in five affected family members (de He er 2011, Schrauwen 2013, LMM data). It has been identified in 0.1% (153/152370) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs370898981). This variant is located in the 5' spli ce region, and RT-PCR analysis of RNA from affected individuals reveals abnormal splicing of TMC1 transcripts resulting in a premature stop codon (de Heer 2011) . In summary, this variant meets criteria to be classified as pathogenic for aut osomal recessive nonsyndromic sensorineural hearing loss. ACMG/AMP Criteria appl ied: PM3_VeryStrong, PP1_Strong, PS3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.56

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.56

Position offset: -3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over