rs612969

Variant names:

• chr11-121118626-A-G
• rs612969
• NM_005422.4:c.1111A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Arg317Gly variant in the TECTA gene is 67.5% (16434/24006) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal dominant and autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA136018/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.48 (18608 hom., cov: 31)
  • Exomes 𝑓: 0.42 (130676 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 4.96
• Publications: 40 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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.1111A>G	p.Arg371Gly	missense	Exon 7 of 24	NP_005413.2	O75443
	TBCEL-TECTA	NM_001378761.1		c.2068A>G	p.Arg690Gly	missense	Exon 13 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.1111A>G	p.Arg371Gly	missense	Exon 7 of 24	ENSP00000376543.1	O75443
	TECTA	ENST00000264037.2	TSL:1	c.1111A>G	p.Arg371Gly	missense	Exon 6 of 23	ENSP00000264037.2	O75443
	TECTA	ENST00000642222.1		c.1111A>G	p.Arg371Gly	missense	Exon 7 of 24	ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72144 AN: 151848 Hom.: 18595 Cov.: 31

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.438

GnomAD2 exomes AF: 0.398 AC: 99962 AN: 251444 AF XY: 0.391

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.332

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.418 AC: 610985 AN: 1461832 Hom.: 130676 Cov.: 63 AF XY: 0.413 AC XY: 300683 AN XY: 727218

African (AFR) AF: 0.695 AC: 23257 AN: 33480

American (AMR) AF: 0.338 AC: 15102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9509 AN: 26136

East Asian (EAS) AF: 0.271 AC: 10747 AN: 39700

South Asian (SAS) AF: 0.318 AC: 27462 AN: 86256

European-Finnish (FIN) AF: 0.467 AC: 24933 AN: 53372

Middle Eastern (MID) AF: 0.320 AC: 1844 AN: 5768

European-Non Finnish (NFE) AF: 0.426 AC: 473581 AN: 1112000

Other (OTH) AF: 0.406 AC: 24550 AN: 60396

GnomAD4 genome AF: 0.475 AC: 72204 AN: 151966 Hom.: 18608 Cov.: 31 AF XY: 0.468 AC XY: 34752 AN XY: 74258

African (AFR) AF: 0.677 AC: 28061 AN: 41428

American (AMR) AF: 0.361 AC: 5513 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1268 AN: 3468

East Asian (EAS) AF: 0.239 AC: 1232 AN: 5154

South Asian (SAS) AF: 0.315 AC: 1516 AN: 4814

European-Finnish (FIN) AF: 0.460 AC: 4847 AN: 10542

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.420 AC: 28517 AN: 67974

Other (OTH) AF: 0.435 AC: 920 AN: 2114

Alfa AF: 0.431 Hom.: 44806

Bravo AF: 0.479

TwinsUK AF: 0.421 AC: 1561

ALSPAC AF: 0.432 AC: 1664

ESP6500AA AF: 0.663 AC: 2922

ESP6500EA AF: 0.412 AC: 3545

ExAC AF: 0.403 AC: 48890

Asia WGS AF: 0.299 AC: 1040 AN: 3478

EpiCase AF: 0.398

EpiControl AF: 0.394

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 12 (2)
-	-	2	Autosomal recessive nonsyndromic hearing loss 21 (2)
-	-	2	not provided (2)
-	-	1	Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.33
DEOGEN2	Benign	0.094	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.037	T
MetaRNN	Benign	0.0000034	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.5	N
PhyloP100		5.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	6.1	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.041
MPC		0.41
ClinPred		0.0020	T
GERP RS		3.9
Varity_R		0.081
gMVP		0.53
Mutation Taster		=97/3	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: rs612969; hg19: chr11-120989335; COSMIC: COSV50693695;