rs542600464

chr11-121168787-C-Achr11-121168787-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005422.4(TECTA):c.5861C>A(p.Thr1954Lys) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1954M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.20

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain ZP (size 254) in uniprot entity TECTA_HUMAN there are 28 pathogenic changes around while only 9 benign (76%) in NM_005422.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.5861C>A	p.Thr1954Lys	missense_variant	20/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.6803C>A	p.Thr2268Lys	missense_variant	26/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.5861C>A	p.Thr1954Lys	missense_variant	20/24	5	NM_005422.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	0.46	N;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Uncertain	0.58
Sift	Benign	0.062	T;.;T
Sift4G	Uncertain	0.0060	D;.;D
Polyphen		0.96	D;.;D
Vest4		0.68
MutPred		0.74		Gain of ubiquitination at T1954 (P = 0.0267);.;Gain of ubiquitination at T1954 (P = 0.0267);
MVP		0.89
MPC		1.0
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.42
gMVP		0.79

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: rs542600464; hg19: chr11-121039496;