rs370898981

chr9-72816213-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_138691.3(TMC1):c.1763+3A>G variant causes a splice donor 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: TMC1 NM_138691.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 B:1
• Conservation: PhyloP100: 5.04

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-72816213-A-G is Pathogenic according to our data. Variant chr9-72816213-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47864.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_benign=1, Likely_pathogenic=1}. 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	UniProt
TMC1	NM_138691.3	c.1763+3A>G		splice_donor_region_variant, intron_variant		ENST00000297784.10
TMC1	XM_017014256.2	c.1766+3A>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.1763+3A>G		splice_donor_region_variant, intron_variant		1	NM_138691.3	P2

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152236 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000663 AC XY: 90 AN XY: 135808

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.: 0 Cov.: 31 AF XY: 0.000755 AC XY: 549 AN XY: 726848

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: 78 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74506

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.: 0

Bravo AF: 0.000438

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5

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	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+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

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

-

- -

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. -

Nonsyndromic Hearing Loss, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
Cadd	Benign	23
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

Other links and lift over

dbSNP: rs370898981; hg19: chr9-75431129;