rs146175803

Positions:

• chr11-121129927-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005422.4(TECTA):​c.2657A>G​(p.Asn886Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,612,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 9.12

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07219997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.2657A>G	p.Asn886Ser	missense_variant	10/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.3614A>G	p.Asn1205Ser	missense_variant	16/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.2657A>G	p.Asn886Ser	missense_variant	10/24	5	NM_005422.4	ENSP00000376543	P4
TECTA	ENST00000264037.2	c.2657A>G	p.Asn886Ser	missense_variant	9/23	1		ENSP00000264037	P4
TECTA	ENST00000642222.1	c.2657A>G	p.Asn886Ser	missense_variant	10/24			ENSP00000493855	A1
TECTA	ENST00000645008.1			upstream_gene_variant				ENSP00000496274

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000475 AC: 119 AN: 250476 Hom.: 0 AF XY: 0.000436 AC XY: 59 AN XY: 135330

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.000821

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000836 AC: 1221 AN: 1460664 Hom.: 1 Cov.: 31 AF XY: 0.000807 AC XY: 586 AN XY: 726478

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.000997

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74470

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000632 Hom.: 0

Bravo AF: 0.000525

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.000709

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2024	Reported in published literature in unrelated individuals with suspected autosomal recessive nonsyndromic hearing loss, each with a second TECTA variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 27068579, 29196752); Reported in published literature in association with autosomal dominant non-syndromic hearing loss in one family, where it was identified in cis with a splicing variant in the TECTA gene in all affected individuals tested (PMID: 21520338); In silico analysis indicates that this missense variant does not alter protein structure/function; Within the ZA, zonadhesin and VWFD2, von Willebrand factor type D2 domains (PMID: 21520338, 31554319, 9590290); This variant is associated with the following publications: (PMID: 25262649, 22995349, 27368438, 30245029, 29196752, 21520338, 27068579, 31554319, 9590290) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 21 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A heterozygous missense variant, NM_005422.2(TECTA):c.2657A>G, has been identified in exon 9 of 23 of the TECTA gene. The variant is predicted to result in a minor amino acid change from asparagine to serine at position 886 of the protein (NP_005413.2(TECTA):p.Asn886Ser). The asparagine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the VWFD 2 functional domain. In silico predictions for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.046% (130 heterozygotes). The variant has been previously described as a VUS and likely benign (ClinVar, Deafnessvariationdatabase, LOVD, Shearer, A. E., et al. (2014), Baux, D., et al. (2017)). An alternative change to histidine has also been reported as a VUS (Deafnessvariationdatabase). Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE with LOW CLINICAL RELEVANCE. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 27, 2019

The p.Asn886Ser variant in TECTA has been previously reported in 7 individuals with sensorineural hearing loss (Baux 2017, Hildebrand 2011, Sommen 2016, Baux 2017, LMM data). In 3 of these individuals a second TECTA variant was identified (p.Glu1950del, p.Val205Leu, p.Cys1372*), though only one was likely to be pathogenic (p.Cys1372*). Furthermore, one of the previously reported probands had a family history of autosomal dominant hearing loss, and while the variant segregated with the disease in 12 affected family members, a more likely pathogenic variant in TECTA (c.5383+5_5383+8delGTGA) was identified in cis with p.Asn886Ser, suggesting that p.Asn886Ser was less likely related to the hearing loss in this family (Hildebrand, 2011). This variant has been identified in 0.07% (98/128646) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Asn886Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to conflicting evidence, the clinical significance of the p.Asn886Ser variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, BS1_Supporting, BP2. -

Autosomal dominant nonsyndromic hearing loss 12;C1863655:Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 08, 2021

- -

Autosomal dominant nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.77	N;.;N
REVEL	Benign	0.23
Sift	Benign	0.23	T;.;T
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.80
MVP		0.74
MPC		0.85
ClinPred		0.080	T
GERP RS		5.7
Varity_R		0.13
gMVP		0.59

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: rs146175803; hg19: chr11-121000636; COSMIC: COSV50713002; COSMIC: COSV50713002;