11-121168101-C-G

Variant names:

• chr11-121168101-C-G
• rs2155369
• NM_005422.4:c.5634C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_005422.4(TECTA):​c.5634C>G​(p.Ser1878Arg) variant causes a missense change involving the alteration of a non-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. Synonymous variant affecting the same amino acid position (i.e. S1878S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610
• Publications: 26 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a disulfide_bond (size 92) in uniprot entity TECTA_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_005422.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4	c.5634C>G	p.Ser1878Arg	missense_variant	Exon 19 of 24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.6576C>G	p.Ser2192Arg	missense_variant	Exon 25 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.5634C>G	p.Ser1878Arg	missense_variant	Exon 19 of 24	5	NM_005422.4	ENSP00000376543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;T
Eigen	Benign	-0.00073
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.6	L;.;L
PhyloP100		-0.061
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.015	D;.;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.80
MutPred		0.76		Gain of MoRF binding (P = 0.0791);.;Gain of MoRF binding (P = 0.0791);
MVP		0.79
MPC		1.1
ClinPred		0.95	D
GERP RS		-0.13
Varity_R		0.39
gMVP		0.83
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs2155369; hg19: chr11-121038810;