rs1555123944

Positions:

• chr11-121127943-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005422.4(TECTA):​c.1966G>A​(p.Gly656Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,808 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.03

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.1966G>A	p.Gly656Ser	missense_variant	9/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.2923G>A	p.Gly975Ser	missense_variant	15/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.1966G>A	p.Gly656Ser	missense_variant	9/24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.1966G>A	p.Gly656Ser	missense_variant	8/23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.1966G>A	p.Gly656Ser	missense_variant	9/24			ENSP00000493855.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 06, 2016

The p.Gly656Ser variant in TECTA has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein. In summary, the clinical significance of the p.Gly656Ser vari ant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D;.;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0060	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.65
MutPred		0.64		Gain of phosphorylation at Y658 (P = 0.2198);Gain of phosphorylation at Y658 (P = 0.2198);Gain of phosphorylation at Y658 (P = 0.2198);
MVP		0.82
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.54
gMVP		0.86

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: rs1555123944; hg19: chr11-120998652;