rs1303790601

Positions:

• chr11-121130010-A-G
• chr11-121130010-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_005422.4(TECTA):​c.2740A>G​(p.Ile914Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.17

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16149396).
• BP6: Variant 11-121130010-A-G is Benign according to our data. Variant chr11-121130010-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 505362.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.2740A>G	p.Ile914Val	missense_variant	10/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.3697A>G	p.Ile1233Val	missense_variant	16/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.2740A>G	p.Ile914Val	missense_variant	10/24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.2740A>G	p.Ile914Val	missense_variant	9/23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.2740A>G	p.Ile914Val	missense_variant	10/24			ENSP00000493855.1
TECTA	ENST00000645008.1	c.46A>G	p.Ile16Val	missense_variant	1/15			ENSP00000496274.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456544 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723600

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2016

p.Ile914Val in exon 9 of TECTA: This variant is not expected to have clinical si gnificance due to a lack of conservation across species. Of note, 4 mammals (Chi nese tree shrew, microbat, David's myotis, and shrew) have a valine (Val) at thi s position despite high nearby amino acid conservation. In addition, computation al prediction tools do not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.50	N;.;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.72	N;.;N
REVEL	Benign	0.087
Sift	Benign	0.10	T;.;T
Sift4G	Benign	0.72	T;.;T
Polyphen		0.0	B;.;B
Vest4		0.092
MutPred		0.59		Gain of catalytic residue at I914 (P = 0.0179);Gain of catalytic residue at I914 (P = 0.0179);Gain of catalytic residue at I914 (P = 0.0179);
MVP		0.75
MPC		0.27
ClinPred		0.083	T
GERP RS		0.70
Varity_R		0.072
gMVP		0.45

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: rs1303790601; hg19: chr11-121000719;