NM_005422.4:c.2795T>C

Variant names:

• chr11-121130065-T-C
• rs520805
• NM_005422.4:c.2795T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005422.4(TECTA):​c.2795T>C​(p.Val932Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,878 control chromosomes in the GnomAD database, including 39,283 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V932L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3231 hom., cov: 33)
  • Exomes 𝑓: 0.22 (36052 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.04
• Publications: 37 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015909076).
• BP6: Variant 11-121130065-T-C is Benign according to our data. Variant chr11-121130065-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

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.2795T>C	p.Val932Ala	missense	Exon 10 of 24	NP_005413.2	O75443
	TBCEL-TECTA	NM_001378761.1		c.3752T>C	p.Val1251Ala	missense	Exon 16 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.2795T>C	p.Val932Ala	missense	Exon 10 of 24	ENSP00000376543.1	O75443
	TECTA	ENST00000264037.2	TSL:1	c.2795T>C	p.Val932Ala	missense	Exon 9 of 23	ENSP00000264037.2	O75443
	TECTA	ENST00000642222.1		c.2795T>C	p.Val932Ala	missense	Exon 10 of 24	ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31090 AN: 152012 Hom.: 3230 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.217 AC: 54409 AN: 251140 AF XY: 0.215

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.247

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.213

GnomAD4 exome AF: 0.220 AC: 322267 AN: 1461748 Hom.: 36052 Cov.: 38 AF XY: 0.220 AC XY: 159741 AN XY: 727166

African (AFR) AF: 0.174 AC: 5809 AN: 33478

American (AMR) AF: 0.229 AC: 10229 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5631 AN: 26134

East Asian (EAS) AF: 0.268 AC: 10633 AN: 39700

South Asian (SAS) AF: 0.201 AC: 17322 AN: 86256

European-Finnish (FIN) AF: 0.247 AC: 13164 AN: 53336

Middle Eastern (MID) AF: 0.176 AC: 1012 AN: 5766

European-Non Finnish (NFE) AF: 0.221 AC: 245730 AN: 1111972

Other (OTH) AF: 0.211 AC: 12737 AN: 60386

GnomAD4 genome AF: 0.204 AC: 31091 AN: 152130 Hom.: 3231 Cov.: 33 AF XY: 0.204 AC XY: 15171 AN XY: 74346

African (AFR) AF: 0.171 AC: 7114 AN: 41512

American (AMR) AF: 0.204 AC: 3126 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3472

East Asian (EAS) AF: 0.234 AC: 1213 AN: 5174

South Asian (SAS) AF: 0.190 AC: 916 AN: 4822

European-Finnish (FIN) AF: 0.243 AC: 2572 AN: 10580

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14866 AN: 67968

Other (OTH) AF: 0.190 AC: 401 AN: 2108

Alfa AF: 0.214 Hom.: 14307

Bravo AF: 0.202

TwinsUK AF: 0.221 AC: 820

ALSPAC AF: 0.224 AC: 865

ESP6500AA AF: 0.175 AC: 771

ESP6500EA AF: 0.210 AC: 1809

ExAC AF: 0.214 AC: 25963

Asia WGS AF: 0.213 AC: 740 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.196

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 12 (2)
-	-	2	Autosomal recessive nonsyndromic hearing loss 21 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.63
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L
PhyloP100		3.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.12
Sift	Benign	0.54	T
Sift4G	Benign	0.73	T
Polyphen		0.0030	B
Vest4		0.055
MPC		0.39
ClinPred		0.0050	T
GERP RS		4.7
PromoterAI		-0.14	Neutral
Varity_R		0.081
gMVP		0.71
Mutation Taster		=93/7	polymorphism (auto)

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: rs520805; hg19: chr11-121000774; COSMIC: COSV50688374;