Genetic Variant NM_005422.4:c.1327C>G (chr11-121125425-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005422.4(TECTA):c.1327C>G(p.His443Asp) 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. H443Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.09

Publications

0 publications found

Variant links:

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]

TECTA links:

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]

TBCEL-TECTA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.774

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005422.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECTA	NM_005422.4	MANE Select	c.1327C>G	p.His443Asp	missense	Exon 8 of 24	NP_005413.2
	TBCEL-TECTA	NM_001378761.1		c.2284C>G	p.His762Asp	missense	Exon 14 of 30	NP_001365690.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TECTA	ENST00000392793.6	TSL:5 MANE Select	c.1327C>G	p.His443Asp	missense	Exon 8 of 24	ENSP00000376543.1
TECTA	ENST00000264037.2	TSL:1	c.1327C>G	p.His443Asp	missense	Exon 7 of 23	ENSP00000264037.2
TECTA	ENST00000642222.1		c.1327C>G	p.His443Asp	missense	Exon 8 of 24	ENSP00000493855.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.2

PhyloP100

6.1

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.39

Sift

Benign

0.23

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.91

MutPred

0.60

Gain of phosphorylation at Y444 (P = 0.1242)

MVP

0.89

MPC

1.3

ClinPred

0.99

GERP RS

4.7

Varity_R

0.62

gMVP

0.93

Mutation Taster

=27/73

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over