TMC1 p.Met411Ile

Variant names:

• chr9-72791894-G-T
• NM_138691.3:c.1233G>T
• TMC1 p.Met411Ile

Your query was ambiguous. Multiple possible variants found:

• chr9-72791894-G-T
• chr9-72791894-G-C
• chr9-72791894-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_138691.3(TMC1):​c.1233G>T​(p.Met411Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M411V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32
• 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD 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 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_138691.3
• 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 autosomal recessive nonsyndromic hearing loss 7, nonsyndromic genetic hearing loss, autosomal dominant nonsyndromic hearing loss 36, hearing loss, autosomal recessive, autosomal dominant nonsyndromic hearing loss.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138691.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	NM_138691.3	MANE Select	c.1233G>T	p.Met411Ile	missense	Exon 16 of 24	NP_619636.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.1233G>T	p.Met411Ile	missense	Exon 16 of 24	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.1233G>T	p.Met411Ile	missense	Exon 14 of 22	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.1233G>T	p.Met411Ile	missense	Exon 15 of 23	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.63
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.41	N
PhyloP100		2.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.1	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.26
gMVP		0.66
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 17
DS_AL_spliceai		0.20		Position offset: -8

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-75406810;