rs147354818

chr11-121160165-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005422.4(TECTA):c.4720A>G(p.Ile1574Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,614,236 control chromosomes in the GnomAD database, including 5 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 1.05

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00861764).
• BP6: Variant 11-121160165-A-G is Benign according to our data. Variant chr11-121160165-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 303027.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00116 (176/152342) while in subpopulation NFE AF= 0.00181 (123/68036). AF 95% confidence interval is 0.00155. There are 1 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.4720A>G	p.Ile1574Val	missense_variant	15/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.5677A>G	p.Ile1893Val	missense_variant	21/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.4720A>G	p.Ile1574Val	missense_variant	15/24	5	NM_005422.4	P4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000506

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: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00118 AC: 296 AN: 251486 Hom.: 1 AF XY: 0.00121 AC XY: 165 AN XY: 135916

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00158 AC: 2306 AN: 1461894 Hom.: 4 Cov.: 32 AF XY: 0.00151 AC XY: 1095 AN XY: 727248

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00279

Gnomad4 NFE exome AF: 0.00181

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00103 AC XY: 77 AN XY: 74502

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.000922

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00126 AC: 153

EpiCase AF: 0.00174

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	Observed in 0.1191% (337/282894 alleles) in large population cohorts (Lek et al., 2016) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.4720A>G (p.I1574V) alteration is located in exon 14 (coding exon 14) of the TECTA gene. This alteration results from a A to G substitution at nucleotide position 4720, causing the isoleucine (I) at amino acid position 1574 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 24, 2017

p.Ile1574Val in exon 14 of TECTA: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, Golden hamster, cat, rabbit, and four other mammals have a valine (Val) a t this position despite high nearby amino acid conservation. It has also been i dentified in 0.2% (63/25794) of Finnish chromosomes and 0.2% (221/126732) of Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org; dbSNP rs147354818). -

TECTA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as likely 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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.4
Dann	Benign	0.38
DEOGEN2	Benign	0.073	T;.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.49	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.20	N;.;N
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.22	N;.;N
REVEL	Benign	0.061
Sift	Benign	0.72	T;.;T
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0010	B;.;B
Vest4		0.23
MVP		0.53
MPC		0.27
ClinPred		0.017	T
GERP RS		1.2
Varity_R		0.044
gMVP		0.085

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: rs147354818; hg19: chr11-121030874;