rs121908072

Positions:

• chr9-72816161-G-A
• chr9-72816161-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_138691.3(TMC1):​c.1714G>A​(p.Asp572Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D572H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_138691.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-72816161-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4105.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 9-72816161-G-A is Pathogenic according to our data. Variant chr9-72816161-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72816161-G-A is described in Lovd as [Likely_pathogenic]. Variant chr9-72816161-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3	c.1714G>A	p.Asp572Asn	missense_variant	19/24	ENST00000297784.10
TMC1	XM_017014256.2	c.1717G>A	p.Asp573Asn	missense_variant	16/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.1714G>A	p.Asp572Asn	missense_variant	19/24	1	NM_138691.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 36 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Sep 28, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 28, 2020	The TMC1 c.1714G>A; p.Asp572Asn variant (rs121908072) is reported in the literature segregating with disease in several families affected with autosomal dominant hearing loss (Hilgert 2009, Kurima 2002, Wang 2018, Wei 2014). This variant is reported in ClinVar (Variation ID: 4102), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1714G>C; p.Asp572His) has been reported in a large family affected with autosomal dominant hearing loss (Kitajiri 2007). Based on available information, this variant is considered to be pathogenic. References: Hilgert N et al. Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. J Hum Genet. 2009;54(3):188-190. Kitajiri S et al. A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. Clin Genet. 2007;71(2):148-152. Kurima et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002 Mar;30(3):277-84. Wang et al. Identification of four TMC1 variations in different Chinese families with hereditary hearing loss. Mol Genet Genomic Med. 2018 Apr 14. Wei Q et al. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J Transl Med. 2014;12:311. Published 2014 Nov 12. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2022	Published functional studies demonstrate a damaging effect: severe disruption of LHFPL5 binding (Yu et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17250663, 15354000, 25388789, 26226225, 26079994, 29654653, 31854501, 31541171, 19180119, 11850618, 33168709, 27535533) -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2015

The p.Asp572Asn in TMC1 has been previously reported in 3 probands with nonsyndr omic bilateral sensorineural hearing loss, and segregated with disease in a domi nant pattern in >10 affected family members (Kurima 2002, Hilgert 2009, Makishim a 2004, Wei 2014). The hearing loss was reported to be progressive with a postli ngual onset. The variant was identified in one unaffected individual from one fa mily, indicating that the penetrance may not be complete; however the age of thi s individual was also not reported (Hilgert 2009). This variant was absent from large population databases. A variant affecting the same amino acid (p.Asp572His ) has also been reported in an individual with hearing loss and segregated in 7 affected family members including 2 obligate carriers (Kitajiri 2007), further s upporting that missense variants at this position are not tolerated. Unlike loss of function variants in TMC1, which cause recessive hearing loss, these studies indicate that the p.Asp572Asn and p.Asp572His missense variants cause dominant hearing loss. In summary, the p.Asp572Asn variant meets our criteria to be class ified as pathogenic for autosomal dominant sensorineural hearing loss (http://ww w.partners.org/personalizedmedicine/LMM) based upon segregation studies in affec ted families and its absence in the general population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;T;.;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.8	L;L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.5	D;.;.;D;.
REVEL	Uncertain	0.47
Sift	Benign	0.12	T;.;.;T;.
Sift4G	Uncertain	0.023	D;.;.;D;.
Polyphen		1.0	D;D;.;D;.
Vest4		0.94
MutPred		0.85		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);.;
MVP		0.77
MPC		0.68
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.53
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908072; hg19: chr9-75431077; COSMIC: COSV52773373;