chr9-72792318-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_138691.3(TMC1):c.1532C>T(p.Pro511Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P511H) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
TMC1
NM_138691.3 missense
NM_138691.3 missense
Scores
3
11
4
Clinical Significance
Conservation
PhyloP100: 4.93
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a topological_domain Cytoplasmic (size 172) in uniprot entity TMC1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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 chr9-72792318-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165436.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
PP5
Variant 9-72792318-C-T is Pathogenic according to our data. Variant chr9-72792318-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 402278.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.1532C>T | p.Pro511Leu | missense_variant | 17/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.1535C>T | p.Pro512Leu | missense_variant | 14/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.1532C>T | p.Pro511Leu | missense_variant | 17/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461854Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727232
GnomAD4 exome
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2
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1461854
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33
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2
AN XY:
727232
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 7 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Hereditary Research Laboratory, Bethlehem University | Jun 04, 2016 | FA3 moderate HL at 6y; FA4 profound at 18m - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;D;.
REVEL
Uncertain
Sift
Benign
T;.;.;T;.
Sift4G
Uncertain
D;.;.;D;.
Polyphen
P;P;.;P;.
Vest4
MutPred
Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);.;Gain of helix (P = 0.0349);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at