rs142948530

chr11-121162110-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005422.4(TECTA):c.5012C>T(p.Ser1671Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00721 in 1,614,188 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1671P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (50 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 7.47

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007885486).
• BP6: Variant 11-121162110-C-T is Benign according to our data. Variant chr11-121162110-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45335.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=1, Uncertain_significance=1}. Variant chr11-121162110-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00637 (971/152376) while in subpopulation NFE AF= 0.00958 (652/68036). AF 95% confidence interval is 0.00897. There are 8 homozygotes in gnomad4. There are 479 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.5012C>T	p.Ser1671Leu	missense_variant	16/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.5954C>T	p.Ser1985Leu	missense_variant	22/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.5012C>T	p.Ser1671Leu	missense_variant	16/24	5	NM_005422.4	P4

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 971 AN: 152258 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00958

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00546 AC: 1371 AN: 251186 Hom.: 7 AF XY: 0.00531 AC XY: 721 AN XY: 135810

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00947

Gnomad NFE exome AF: 0.00773

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00730 AC: 10669 AN: 1461812 Hom.: 50 Cov.: 30 AF XY: 0.00721 AC XY: 5244 AN XY: 727216

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.00914

Gnomad4 NFE exome AF: 0.00829

Gnomad4 OTH exome AF: 0.00603

GnomAD4 genome AF: 0.00637 AC: 971 AN: 152376 Hom.: 8 Cov.: 31 AF XY: 0.00643 AC XY: 479 AN XY: 74522

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.00958

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00803 Hom.: 9

Bravo AF: 0.00522

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00768 AC: 66

ExAC AF: 0.00505 AC: 613

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser1671Leu in Exon 15 of TECTA: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (52/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs142948530). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TECTA: BS2 -

Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

TECTA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant nonsyndromic hearing loss 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;T
Eigen	Benign	0.057
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0079	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.17	T;.;T
Sift4G	Benign	0.16	T;.;T
Polyphen		0.17	B;.;B
Vest4		0.63
MVP		0.71
MPC		0.31
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.55

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: rs142948530; hg19: chr11-121032819; COSMIC: COSV50755443;