11-121129648-A-G

Variant names:

• chr11-121129648-A-G
• rs727503459
• NM_005422.4:c.2378A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005422.4(TECTA):​c.2378A>G​(p.Gln793Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27050602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4	c.2378A>G	p.Gln793Arg	missense_variant	Exon 10 of 24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.3335A>G	p.Gln1112Arg	missense_variant	Exon 16 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.2378A>G	p.Gln793Arg	missense_variant	Exon 10 of 24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.2378A>G	p.Gln793Arg	missense_variant	Exon 9 of 23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.2378A>G	p.Gln793Arg	missense_variant	Exon 10 of 24			ENSP00000493855.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gln793Arg variant in TECTA has not been previously reported in individuals w ith hearing loss or in large population studies. The glutamine (Gln) at position 793 is not conserved in evolutionarily distant species and one mammal (naked mo le rat) carries an arginine (Arg) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools suggest that this variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. In summary, while the clinical signif icance of the Gln793Arg variant is uncertain, the conservation data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;T
Eigen	Benign	0.051
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.34	T;.;T
Sift4G	Benign	0.14	T;.;T
Polyphen		0.49	P;.;P
Vest4		0.14
MutPred		0.59		Gain of methylation at Q793 (P = 0.0732);Gain of methylation at Q793 (P = 0.0732);Gain of methylation at Q793 (P = 0.0732);
MVP		0.61
MPC		0.51
ClinPred		0.64	D
GERP RS		5.2
Varity_R		0.20
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs727503459; hg19: chr11-121000357;