rs121909059

chr11-121137648-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_005422.4(TECTA):c.3169T>A(p.Cys1057Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,872 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.28

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 11-121137648-T-A is Pathogenic according to our data. Variant chr11-121137648-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7016.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-121137648-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.3169T>A	p.Cys1057Ser	missense_variant	11/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.4126T>A	p.Cys1376Ser	missense_variant	17/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.3169T>A	p.Cys1057Ser	missense_variant	11/24	5	NM_005422.4	P4
TECTA	ENST00000264037.2	c.3169T>A	p.Cys1057Ser	missense_variant	10/23	1		P4
TECTA	ENST00000642222.1	c.3169T>A	p.Cys1057Ser	missense_variant	11/24			A1
TECTA	ENST00000645008.1	c.478T>A	p.Cys160Ser	missense_variant	2/15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251226 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 12 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Apr 05, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1999	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	3.2	M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.5	D;.;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.71		Gain of catalytic residue at C1057 (P = 0.0356);Gain of catalytic residue at C1057 (P = 0.0356);Gain of catalytic residue at C1057 (P = 0.0356);
MVP		0.92
MPC		0.56
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121909059; hg19: chr11-121008357;