rs750620981

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_005422.4(TECTA):​c.2726G>A​(p.Arg909His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,605,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

3
7
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.23
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TECTANM_005422.4 linkuse as main transcriptc.2726G>A p.Arg909His missense_variant 10/24 ENST00000392793.6 NP_005413.2
TBCEL-TECTANM_001378761.1 linkuse as main transcriptc.3683G>A p.Arg1228His missense_variant 16/30 NP_001365690.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TECTAENST00000392793.6 linkuse as main transcriptc.2726G>A p.Arg909His missense_variant 10/245 NM_005422.4 ENSP00000376543 P4
TECTAENST00000264037.2 linkuse as main transcriptc.2726G>A p.Arg909His missense_variant 9/231 ENSP00000264037 P4
TECTAENST00000642222.1 linkuse as main transcriptc.2726G>A p.Arg909His missense_variant 10/24 ENSP00000493855 A1
TECTAENST00000645008.1 linkuse as main transcriptc.35G>A p.Arg12His missense_variant 1/15 ENSP00000496274

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000243
AC:
6
AN:
247216
Hom.:
0
AF XY:
0.0000300
AC XY:
4
AN XY:
133438
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000358
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1453772
Hom.:
0
Cov.:
30
AF XY:
0.0000139
AC XY:
10
AN XY:
721856
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000226
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000506
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 13, 2017The p.Arg909His variant in TECTA has not been previously reported in individuals with hearing loss, but has been identified in 4/109684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSN P rs750620981). Although this variant has been seen in the general population, i ts frequency is not high enough to rule out a pathogenic role. Computational pre diction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. In summary, the clinical significance of the p.Arg909His variant is un certain. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 02, 2024The c.2726G>A (p.R909H) alteration is located in exon 9 (coding exon 9) of the TECTA gene. This alteration results from a G to A substitution at nucleotide position 2726, causing the arginine (R) at amino acid position 909 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.017
T
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.18
T;.;T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.93
.;D;D
M_CAP
Benign
0.037
D
MetaRNN
Uncertain
0.62
D;D;D
MetaSVM
Uncertain
0.073
D
MutationAssessor
Benign
0.90
L;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.1
N;.;N
REVEL
Uncertain
0.42
Sift
Benign
0.087
T;.;T
Sift4G
Benign
0.16
T;.;T
Polyphen
1.0
D;.;D
Vest4
0.56
MutPred
0.69
Gain of ubiquitination at K904 (P = 0.0605);Gain of ubiquitination at K904 (P = 0.0605);Gain of ubiquitination at K904 (P = 0.0605);
MVP
0.92
MPC
0.52
ClinPred
0.43
T
GERP RS
5.8
Varity_R
0.29
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs750620981; hg19: chr11-121000705; API