rs121909058

chr11-121168076-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_005422.4(TECTA):c.5609A>G(p.Tyr1870Cys) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.91

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a disulfide_bond (size 92) in uniprot entity TECTA_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_005422.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 11-121168076-A-G is Pathogenic according to our data. Variant chr11-121168076-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7014.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.5609A>G	p.Tyr1870Cys	missense_variant	19/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.6551A>G	p.Tyr2184Cys	missense_variant	25/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.5609A>G	p.Tyr1870Cys	missense_variant	19/24	5	NM_005422.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 12 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	TECTA c.5609A>G, p.Y1870C is the original mutation responsible for dominantly inherited hearing loss due to TECTA (Nat Genet 1998). The variant alters a residue that is completely conserved in all sequenced vertebrates. It is heterozygous in 2 children with moderate to severe hearing loss from a Palestinian family with dominantly inherited hearing loss documented in 4 generations (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1998	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.7	N;.;N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.97
MutPred		0.89		Gain of methylation at K1871 (P = 0.0129);.;Gain of methylation at K1871 (P = 0.0129);
MVP		0.98
MPC		1.2
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.77
gMVP		0.88

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: rs121909058; hg19: chr11-121038785;