11-121189171-T-C

Position:

• chr11-121189171-T-C

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.6250+4T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,560 control chromosomes in the GnomAD database, including 32 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 0.0076 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (12 hom.)
• Consequence: TECTA NM_005422.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00004031
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.458

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 (BayesDel_noAF=-0.69).
• BP6: Variant 11-121189171-T-C is Benign according to our data. Variant chr11-121189171-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45342.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00756 (1151/152294) while in subpopulation AFR AF= 0.0251 (1045/41560). AF 95% confidence interval is 0.0239. There are 20 homozygotes in gnomad4. There are 544 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.6250+4T>C		splice_donor_region_variant, intron_variant		ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.7192+4T>C		splice_donor_region_variant, intron_variant			NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.6250+4T>C		splice_donor_region_variant, intron_variant		5	NM_005422.4	ENSP00000376543	P4

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1151 AN: 152176 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00208 AC: 522 AN: 251462 Hom.: 7 AF XY: 0.00146 AC XY: 198 AN XY: 135908

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000799 AC: 1168 AN: 1461266 Hom.: 12 Cov.: 31 AF XY: 0.000707 AC XY: 514 AN XY: 726994

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00756 AC: 1151 AN: 152294 Hom.: 20 Cov.: 32 AF XY: 0.00730 AC XY: 544 AN XY: 74478

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00358 Hom.: 1

Bravo AF: 0.00878

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 15, 2022	- -

Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

6250+4T>C in Intron 21 of TECTA: This variant is not expected to have clinical s ignificance because it has been identified in 2.7% (101/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs143302176). -

Autosomal dominant nonsyndromic hearing loss 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.93
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0
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: rs143302176; hg19: chr11-121059880;