NM_005422.4:c.2134G>C

Variant names:

• chr11-121128111-G-C
• rs876657587
• NM_005422.4:c.2134G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_005422.4(TECTA):​c.2134G>C​(p.Val712Leu) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.872
• Publications: 4 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15580192).
• BP6: Variant 11-121128111-G-C is Benign according to our data. Variant chr11-121128111-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227989.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4	c.2134G>C	p.Val712Leu	missense_variant	Exon 9 of 24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.3091G>C	p.Val1031Leu	missense_variant	Exon 15 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.2134G>C	p.Val712Leu	missense_variant	Exon 9 of 24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.2134G>C	p.Val712Leu	missense_variant	Exon 8 of 23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.2134G>C	p.Val712Leu	missense_variant	Exon 9 of 24			ENSP00000493855.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val712Leu in exon 8 of TECTA: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, three mammals and 10 evolutionarily distant species (birds and reptiles) ha ve a leucine (L) at this position. In addition, computational prediction tools d o not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.26	T;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.11	N;.;N
PhyloP100		0.87
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.033
Sift	Benign	0.26	T;.;T
Sift4G	Benign	0.65	T;.;T
Polyphen		0.0040	B;.;B
Vest4		0.097
MutPred		0.38		Loss of methylation at K708 (P = 0.0768);Loss of methylation at K708 (P = 0.0768);Loss of methylation at K708 (P = 0.0768);
MVP		0.32
MPC		0.32
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.16
gMVP		0.73
Mutation Taster		=77/23	polymorphism

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: rs876657587; hg19: chr11-120998820;