rs144343770

Variant names:

• chr11-121168762-T-C
• rs144343770
• NM_005422.4:c.5836T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS1 PP3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.5836T>C (p.Tyr1946His) variant in the TECTA gene is 0.495% for Ashkenazi Jewish chromosomes by gnomAD (64/10370 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL EP) for autosomal recessive hearing loss variants (BS1). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3. The HL EP allows classification of variants as likely benign with only BS1 if no other criteria are in conflict. The HL EP reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case since computational scores are error prone, especially when predicting pathogenicity. In summary, the HL EP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA178113/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:6
• Conservation: PhyloP100: 7.64
• Publications: 7 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: Likely_benign. The variant received -3 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.5836T>C	p.Tyr1946His	missense	Exon 20 of 24	NP_005413.2	O75443
	TBCEL-TECTA	NM_001378761.1		c.6778T>C	p.Tyr2260His	missense	Exon 26 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.5836T>C	p.Tyr1946His	missense	Exon 20 of 24	ENSP00000376543.1	O75443
	TECTA	ENST00000264037.2	TSL:1	c.5836T>C	p.Tyr1946His	missense	Exon 19 of 23	ENSP00000264037.2	O75443
	TECTA	ENST00000642222.1		c.5821T>C	p.Tyr1941His	missense	Exon 20 of 24	ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000493 AC: 124 AN: 251460 AF XY: 0.000456

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000298 AC: 436 AN: 1461880 Hom.: 1 Cov.: 31 AF XY: 0.000314 AC XY: 228 AN XY: 727240

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00677 AC: 177 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000141 AC: 157 AN: 1111998

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74476

African (AFR) AF: 0.000144 AC: 6 AN: 41578

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000391 Hom.: 1

Bravo AF: 0.000514

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.032	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.93
MPC		1.2
ClinPred		0.055	T
GERP RS		5.8
Varity_R		0.71
gMVP		0.80
Mutation Taster		=79/21	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: rs144343770; hg19: chr11-121039471;