NM_005422.4:c.907G>C

Variant names:

• chr11-121118422-G-C
• rs774583320
• NM_005422.4:c.907G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005422.4(TECTA):​c.907G>C​(p.Glu303Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4	c.907G>C	p.Glu303Gln	missense_variant	Exon 7 of 24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.1864G>C	p.Glu622Gln	missense_variant	Exon 13 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.907G>C	p.Glu303Gln	missense_variant	Exon 7 of 24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.907G>C	p.Glu303Gln	missense_variant	Exon 6 of 23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.907G>C	p.Glu303Gln	missense_variant	Exon 7 of 24			ENSP00000493855.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251448 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TECTA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 303 of the TECTA protein (p.Glu303Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	L;.;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.28
Sift	Benign	0.22	T;.;T
Sift4G	Uncertain	0.026	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.29
MutPred		0.45		Loss of ubiquitination at K308 (P = 0.1264);Loss of ubiquitination at K308 (P = 0.1264);Loss of ubiquitination at K308 (P = 0.1264);
MVP		0.88
MPC		0.34
ClinPred		0.67	D
GERP RS		5.7
Varity_R		0.27
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs774583320; hg19: chr11-120989131;