rs1184726805

Positions:

• chr11-121137919-A-G

Variant summary

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

The NM_005422.4(TECTA):​c.3440A>G​(p.Asn1147Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,451,908 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: 0.0000014 (0 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29

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/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.3440A>G	p.Asn1147Ser	missense_variant	11/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.4397A>G	p.Asn1466Ser	missense_variant	17/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.3440A>G	p.Asn1147Ser	missense_variant	11/24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.3440A>G	p.Asn1147Ser	missense_variant	10/23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.3440A>G	p.Asn1147Ser	missense_variant	11/24			ENSP00000493855.1
TECTA	ENST00000645008.1	c.746A>G	p.Asn249Ser	missense_variant	2/15			ENSP00000496274.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451908 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 16, 2017

The p.Asn1147Ser variant in TECTA has not been previously reported in individual s with hearing loss or in large population studies. Splice prediction tools indi cate the possible creation of a cryptic splice site; however, this information i s not predictive enough to determine pathogenicity. Additional computational pr ediction tools and conservation analysis do not provide strong support for or ag ainst an impact to the protein. In summary, the clinical significance of the p.A sn1147Ser variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	.;T;T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.0	D;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.027	D;.;D
Sift4G	Benign	0.12	T;.;T
Polyphen		0.23	B;.;B
Vest4		0.51
MutPred		0.59		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.71
MPC		0.39
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.38
gMVP		0.81

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: rs1184726805; hg19: chr11-121008628;