rs775428246

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_138691.3(TMC1):c.236+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000237 in 1,604,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TMC1
NM_138691.3 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.77

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-72694715-G-A is Pathogenic according to our data. Variant chr9-72694715-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 504715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72694715-G-A 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.236+1G>A		splice_donor_variant		ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2 linkuse as main transcript	c.239+1G>A		splice_donor_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.236+1G>A		splice_donor_variant		1	NM_138691.3	ENSP00000297784	P2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

235618

Hom.:

AF XY:

0.0000315

AC XY:

AN XY:

127136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000585

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000191

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000248

AC:

AN:

1452776

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

722002

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000588

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000172

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 03, 2023	This sequence change affects a donor splice site in intron 7 of the TMC1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMC1 are known to be pathogenic (PMID: 11850618, 22105175). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with autosomal recessive deafness (PMID: 18616530, 23767834, 31028865, 31541171). ClinVar contains an entry for this variant (Variation ID: 504715). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 31541171, 18616530, 31028865, 21250555, 31589614, 33205915, 23767834, 27344577) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Autosomal recessive nonsyndromic hearing loss 7

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -

Autosomal dominant nonsyndromic hearing loss 36

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Hearing loss, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Human Genetics, Universidade de São Paulo

May 01, 2024

The NM_138691.2:c.[236+1G>A] variant is a null variant in a gene where loss of function is a known mechanism of disease (PVS1), Extremely low frequency in gnomAD population databases (PM2), For recessive disorders, detected in trans with a pathogenic variant, or in a homozygous or compound heterozygous state in affected cases (PM3), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), reported in ClinVar in affected individuals (PP5), Here it was found in trans with c.1094G>A in two affected siblings, born from unaffected unrelated couple. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 27, 2016

The c.236+1G>A variant in TMC1 has been reported in 2 homozygous individuals wit h autosomal recessive nonsyndromic sensorineural hearing loss and segregated wit h hearing loss in 4 affected relatives from those 2 families (Hilgert 2008, Hild ebrand 2010). Another variant at the same position c.236+1G>C has also been repo rted as pathogenic in the literature (Yang 2013). This variant has been identifi ed in 1/42270 European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs775428246). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. This variant occurs in the invariant region (+ /- 1/2) of the splice consensus sequence and is predicted to cause altered splic ing leading to an abnormal or absent protein. Loss of function of the TMC1 gene is an established disease mechanism in autosomal recessive nonsyndromic sensorin eural hearing loss. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive nonsyndromic sensorineural hearing loss. -

Ear malformation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D;D

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.92

Position offset: -1

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