chr11-121118644-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B.

Score: 4 - Uncertain Significance
4
-12 -7 -6 -1 0 5 6 9 10 12
PM2PP3_Moderate

The NM_005422.4(TECTA):​c.1129T>C​(p.Trp377Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.95

Publications

0 publications found
Variant links:
Genes affected
TECTA (HGNC:11720): (tectorin alpha) The tectorial membrane is an extracellular matrix of the inner ear that contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals. Alpha-tectorin is one of the major noncollagenous components of the tectorial membrane. Mutations in the TECTA gene have been shown to be responsible for autosomal dominant nonsyndromic hearing impairment and a recessive form of sensorineural pre-lingual non-syndromic deafness. [provided by RefSeq, Jul 2008]
TBCEL-TECTA (HGNC:54857): (TBCEL-TECTA readthrough) Predicted to enable alpha-tubulin binding activity. Predicted to be involved in microtubule cytoskeleton organization; post-chaperonin tubulin folding pathway; and tubulin complex assembly. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TECTANM_005422.4 linkc.1129T>C p.Trp377Arg missense_variant Exon 7 of 24 ENST00000392793.6 NP_005413.2 O75443
TBCEL-TECTANM_001378761.1 linkc.2086T>C p.Trp696Arg missense_variant Exon 13 of 30 NP_001365690.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TECTAENST00000392793.6 linkc.1129T>C p.Trp377Arg missense_variant Exon 7 of 24 5 NM_005422.4 ENSP00000376543.1 O75443
TECTAENST00000264037.2 linkc.1129T>C p.Trp377Arg missense_variant Exon 6 of 23 1 ENSP00000264037.2 O75443
TECTAENST00000642222.1 linkc.1129T>C p.Trp377Arg missense_variant Exon 7 of 24 ENSP00000493855.1 A0A2R8YDL0

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00110
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
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461784
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727184
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53370
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111956
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 25, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Trp377Arg variant in TECTA has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analyses suggest that the p.Trp377Arg variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, the clinical significance of the p.Trp377Arg variant is uncert ain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.39
T;.;T
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.58
.;T;T
M_CAP
Benign
0.046
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Benign
-0.46
T
MutationAssessor
Uncertain
2.8
M;.;M
PhyloP100
5.9
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-7.3
D;.;D
REVEL
Uncertain
0.55
Sift
Pathogenic
0.0
D;.;D
Sift4G
Uncertain
0.0020
D;.;D
Polyphen
0.97
D;.;D
Vest4
0.94
MutPred
0.70
Gain of disorder (P = 0.0011);Gain of disorder (P = 0.0011);Gain of disorder (P = 0.0011);
MVP
0.86
MPC
1.1
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.90
gMVP
0.88
Mutation Taster
=27/73
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs876658013; hg19: chr11-120989353; API