11-121168101-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005422.4(TECTA):c.5634C>T(p.Ser1878=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,613,960 control chromosomes in the GnomAD database, including 19,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1559 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17589 hom.)
• Consequence: TECTA NM_005422.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0610

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 11-121168101-C-T is Benign according to our data. Variant chr11-121168101-C-T is described in ClinVar as [Benign]. Clinvar id is 45338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121168101-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.061 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.5634C>T	p.Ser1878=	synonymous_variant	19/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.6576C>T	p.Ser2192=	synonymous_variant	25/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.5634C>T	p.Ser1878=	synonymous_variant	19/24	5	NM_005422.4	P4

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18215 AN: 152068 Hom.: 1556 Cov.: 32

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.170 AC: 42809 AN: 251466 Hom.: 4603 AF XY: 0.176 AC XY: 23985 AN XY: 135906

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.298

Gnomad SAS exome AF: 0.317

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.141 AC: 206629 AN: 1461774 Hom.: 17589 Cov.: 33 AF XY: 0.148 AC XY: 107673 AN XY: 727188

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.290

Gnomad4 SAS exome AF: 0.313

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.120 AC: 18223 AN: 152186 Hom.: 1559 Cov.: 32 AF XY: 0.125 AC XY: 9330 AN XY: 74424

Gnomad4 AFR AF: 0.0335

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.155

Alfa AF: 0.137 Hom.: 2744

Bravo AF: 0.117

Asia WGS AF: 0.279 AC: 972 AN: 3478

EpiCase AF: 0.144

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ser1878Ser in Exon 18 of TECTA: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 13.3% (935/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2155369). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Autosomal recessive nonsyndromic hearing loss 21 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Autosomal dominant nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	8.5
Dann	Benign	0.69

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: rs2155369; hg19: chr11-121038810; COSMIC: COSV50715554;