rs186780639

Variant names:

• chr11-121137990-G-A
• rs186780639
• NM_005422.4:c.3511G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005422.4(TECTA):​c.3511G>A​(p.Val1171Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,613,716 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene TECTA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.95
• Publications: 5 publications found

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:54857): (TBCEL-TECTA readthrough) Predicted to enable alpha-tubulin binding activity. Predicted to be involved in microtubule cytoskeleton organization; post-chaperonin tubulin folding pathway; and tubulin complex assembly. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Specifications for TECTA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012463182).
• BP6: Variant 11-121137990-G-A is Benign according to our data. Variant chr11-121137990-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 303015.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000158 (24/152346) while in subpopulation EAS AF = 0.00463 (24/5186). AF 95% confidence interval is 0.00319. There are 1 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005422.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECTA	NM_005422.4	MANE Select	c.3511G>A	p.Val1171Met	missense	Exon 11 of 24	NP_005413.2	O75443
	TBCEL-TECTA	NM_001378761.1		c.4468G>A	p.Val1490Met	missense	Exon 17 of 30	NP_001365690.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECTA	ENST00000392793.6	TSL:5 MANE Select	c.3511G>A	p.Val1171Met	missense	Exon 11 of 24	ENSP00000376543.1	O75443
	TECTA	ENST00000264037.2	TSL:1	c.3511G>A	p.Val1171Met	missense	Exon 10 of 23	ENSP00000264037.2	O75443
	TECTA	ENST00000642222.1		c.3511G>A	p.Val1171Met	missense	Exon 11 of 24	ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000234 AC: 58 AN: 247956 AF XY: 0.000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00299

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461370 Hom.: 2 Cov.: 32 AF XY: 0.000237 AC XY: 172 AN XY: 726868

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00875 AC: 347 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111604

Other (OTH) AF: 0.0000331 AC: 2 AN: 60380

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000249 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 12 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 21 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.20
Sift	Benign	0.17	T
Sift4G	Benign	0.093	T
Polyphen		0.97	D
Vest4		0.30
MVP		0.82
MPC		0.89
ClinPred		0.16	T
GERP RS		4.6
Varity_R		0.079
gMVP		0.65
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs186780639; hg19: chr11-121008699; COSMIC: COSV50703487; COSMIC: COSV50703487;