11-121168135-C-G

Position:

• chr11-121168135-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_005422.4(TECTA):​c.5668C>G​(p.Arg1890Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R1890C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain ZP (size 254) in uniprot entity TECTA_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_005422.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-121168135-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.5668C>G	p.Arg1890Gly	missense_variant	19/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.6610C>G	p.Arg2204Gly	missense_variant	25/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.5668C>G	p.Arg1890Gly	missense_variant	19/24	5	NM_005422.4	ENSP00000376543	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.0060	D;.;D
Polyphen		0.99	D;.;D
Vest4		0.65
MutPred		0.68		Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);
MVP		0.92
MPC		0.83
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.57
gMVP		0.50

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: rs121909063; hg19: chr11-121038844;