rs146965680

Variant names:

• chr11-121190796-C-T
• rs146965680
• NM_005422.4:c.6458C>T

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.6458C>T​(p.Thr2153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,611,030 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2153T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (23 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0500
• 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]

ENSG00000299284 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035436153).
• BP6: Variant 11-121190796-C-T is Benign according to our data. Variant chr11-121190796-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 303047.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000736 (112/152272) while in subpopulation SAS AF = 0.0197 (95/4828). AF 95% confidence interval is 0.0165. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR,AD 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.6458C>T	p.Thr2153Met	missense	Exon 24 of 24	NP_005413.2	O75443
	TBCEL-TECTA	NM_001378761.1		c.7400C>T	p.Thr2467Met	missense	Exon 30 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.6458C>T	p.Thr2153Met	missense	Exon 24 of 24	ENSP00000376543.1	O75443
	TECTA	ENST00000264037.2	TSL:1	c.6458C>T	p.Thr2153Met	missense	Exon 23 of 23	ENSP00000264037.2	O75443
	TECTA	ENST00000642222.1		c.6443C>T	p.Thr2148Met	missense	Exon 24 of 24	ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 111 AN: 152154 Hom.: 0 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: 0.000769

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00261 AC: 653 AN: 250550 AF XY: 0.00331

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00135 AC: 1974 AN: 1458758 Hom.: 23 Cov.: 29 AF XY: 0.00188 AC XY: 1361 AN XY: 725780

African (AFR) AF: 0.0000299 AC: 1 AN: 33418

American (AMR) AF: 0.0000224 AC: 1 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00277 AC: 110 AN: 39672

South Asian (SAS) AF: 0.0199 AC: 1714 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52858

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5762

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1109880

Other (OTH) AF: 0.00138 AC: 83 AN: 60290

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00298 AC: 362

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	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	0.080
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.0
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.050
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.094
Sift	Benign	0.30	T
Sift4G	Benign	0.076	T
Polyphen		0.0	B
Vest4		0.060
MVP		0.31
MPC		0.33
ClinPred		0.0074	T
GERP RS		-0.15
Varity_R		0.021
gMVP		0.40
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs146965680; hg19: chr11-121061505;