rs368627411

chr11-121113065-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_005422.4(TECTA):c.487-7C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: TECTA NM_005422.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.02465
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: -0.354

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 11-121113065-C-G is Benign according to our data. Variant chr11-121113065-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 229304.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000554 (81/1461774) while in subpopulation MID AF= 0.00607 (35/5768). AF 95% confidence interval is 0.00448. There are 0 homozygotes in gnomad4_exome. There are 36 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.487-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.1444-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.487-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_005422.4	P4
TECTA	ENST00000264037.2	c.487-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P4
TECTA	ENST00000642222.1	c.487-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				A1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251206 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000554 AC: 81 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2015	Variant classified as Uncertain Significance - Favor Benign. The c.487-7C>G vari ant in TECTA has been previously identified in our laboratory in one individual with hearing loss. This variant has been identified in several populations and was present in 10/120696 of the total chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs368627411). This variant is located in the 3' splice region. Computational tools do not suggest an impact t o splicing; however, this information is not predictive enough to rule out patho genicity. In summary, while the clinical significance of the c.487-7C>G variant is uncertain, these data suggest it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 01, 2016	- -

Nonsyndromic genetic hearing loss Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Oct 02, 2019

The c.487-7C>G intronic variant in TECTA was present in 0.05081% (18/35428) of Latino alleles in gnomAD; however, because this gene has been associated with both AR and AD hearing loss, no criteria were applied based on population data. This variant was identified in 1 white patient with nonsyndromic hearing loss (PS4 not met; Laboratory for Molecular Medicine internal data, SCV000272492.3). The c.487-7C>G variant is classified as likely benign because a C>G change at this position does not diverge from the splice consensus sequence, making it unlikely to impact splicing, and computational splice prediction tools do not predict an impact on splicing. ACMG/AMP Criteria applied, as specified by the Hearing Loss Expert Panel: BP4, BP7. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	8.3
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.025
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.020		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: rs368627411; hg19: chr11-120983774;