rs142948530

Variant names:

• chr11-121162110-C-T
• rs142948530
• NM_005422.4:c.5012C>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.5012C>T​(p.Ser1671Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00721 in 1,614,188 control chromosomes in the GnomAD database, including 58 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1671P) has been classified as Uncertain significance. The gene TECTA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0064 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (50 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 7.47
• Publications: 13 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=0.007885486).
• BP6: Variant 11-121162110-C-T is Benign according to our data. Variant chr11-121162110-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45335.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00637 (971/152376) while in subpopulation NFE AF = 0.00958 (652/68036). AF 95% confidence interval is 0.00897. There are 8 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.5012C>T	p.Ser1671Leu	missense	Exon 16 of 24	NP_005413.2	O75443
	TBCEL-TECTA	NM_001378761.1		c.5954C>T	p.Ser1985Leu	missense	Exon 22 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.5012C>T	p.Ser1671Leu	missense	Exon 16 of 24	ENSP00000376543.1	O75443
	TECTA	ENST00000264037.2	TSL:1	c.5012C>T	p.Ser1671Leu	missense	Exon 15 of 23	ENSP00000264037.2	O75443
	TECTA	ENST00000642222.1		c.4997C>T	p.Ser1666Leu	missense	Exon 16 of 24	ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 971 AN: 152258 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00958

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00546 AC: 1371 AN: 251186 AF XY: 0.00531

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00947

Gnomad NFE exome AF: 0.00773

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00730 AC: 10669 AN: 1461812 Hom.: 50 Cov.: 30 AF XY: 0.00721 AC XY: 5244 AN XY: 727216

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.00246 AC: 110 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 386 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86246

European-Finnish (FIN) AF: 0.00914 AC: 488 AN: 53366

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5754

European-Non Finnish (NFE) AF: 0.00829 AC: 9214 AN: 1112010

Other (OTH) AF: 0.00603 AC: 364 AN: 60396

GnomAD4 genome AF: 0.00637 AC: 971 AN: 152376 Hom.: 8 Cov.: 31 AF XY: 0.00643 AC XY: 479 AN XY: 74522

African (AFR) AF: 0.00113 AC: 47 AN: 41588

American (AMR) AF: 0.00712 AC: 109 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0103 AC: 110 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00958 AC: 652 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00766 Hom.: 13

Bravo AF: 0.00522

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00768 AC: 66

ExAC AF: 0.00505 AC: 613

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 12 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 21 (1)
-	-	1	TECTA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.057
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.16	T
Polyphen		0.17	B
Vest4		0.63
MVP		0.71
MPC		0.31
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.55
Mutation Taster		=44/56	disease causing

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: rs142948530; hg19: chr11-121032819; COSMIC: COSV50755443;