11-121130022-C-T

Position:

• chr11-121130022-C-T

Variant summary

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

The NM_005422.4(TECTA):​c.2752C>T​(p.Pro918Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74

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, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.2752C>T	p.Pro918Ser	missense_variant	10/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.3709C>T	p.Pro1237Ser	missense_variant	16/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.2752C>T	p.Pro918Ser	missense_variant	10/24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.2752C>T	p.Pro918Ser	missense_variant	9/23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.2752C>T	p.Pro918Ser	missense_variant	10/24			ENSP00000493855.1
TECTA	ENST00000645008.1	c.58C>T	p.Pro20Ser	missense_variant	1/15			ENSP00000496274.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.046	D
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.016	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.73
MutPred		0.50		Gain of catalytic residue at P918 (P = 0.0632);Gain of catalytic residue at P918 (P = 0.0632);Gain of catalytic residue at P918 (P = 0.0632);
MVP		0.94
MPC		0.67
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.29
gMVP		0.80

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: rs876658016; hg19: chr11-121000731;