chr9-72788476-A-C

Variant names:

• chr9-72788476-A-C
• rs727504568
• NM_138691.3:c.1022A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_138691.3(TMC1):​c.1022A>C​(p.Asn341Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20
• Publications: 0 publications found

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: AR, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.85843 (below the threshold of 3.09). Trascript score misZ: 1.5687 (below the threshold of 3.09). GenCC associations: The gene is linked to nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36, hearing loss, autosomal recessive, autosomal dominant nonsyndromic hearing loss.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21547005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.1022A>C	p.Asn341Thr	missense_variant	Exon 14 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.1025A>C	p.Asn342Thr	missense_variant	Exon 11 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.1022A>C	p.Asn341Thr	missense_variant	Exon 14 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Asn341Thr varia nt in TMC1 has not been reported in individuals with hearing loss or in large po pulation studies. Computational analyses (biochemical amino acid properties, con servation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Asn341Thr variant ma y not impact the protein, though this information is not predictive enough to ru le out pathogenicity. In summary, additional information is needed to determine the clinical significance of the Asn341Thr variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.;T;.
Eigen	Benign	-0.058
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	.;.;D;D;D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.;L;.
PhyloP100		6.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.75	N;.;.;N;.
REVEL	Benign	0.11
Sift	Benign	0.12	T;.;.;T;.
Sift4G	Uncertain	0.0030	D;.;.;D;.
Polyphen		0.032	B;B;.;B;.
Vest4		0.46
MutPred		0.35		Loss of ubiquitination at K343 (P = 0.0896);Loss of ubiquitination at K343 (P = 0.0896);.;Loss of ubiquitination at K343 (P = 0.0896);.;
MVP		0.65
MPC		0.17
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.10
gMVP		0.27
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs727504568; hg19: chr9-75403392;