NM_005422.4:c.2657A>G

Variant names:

• chr11-121129927-A-G
• rs146175803
• NM_005422.4:c.2657A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_005422.4(TECTA):​c.2657A>G​(p.Asn886Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,612,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 9.12
• Publications: 9 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07219997).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000604 (92/152298) while in subpopulation NFE AF = 0.000956 (65/68022). AF 95% confidence interval is 0.000769. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2657A>G	p.Asn886Ser	missense	Exon 10 of 24	NP_005413.2	O75443
	TBCEL-TECTA	NM_001378761.1		c.3614A>G	p.Asn1205Ser	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.2657A>G	p.Asn886Ser	missense	Exon 10 of 24	ENSP00000376543.1	O75443
	TECTA	ENST00000264037.2	TSL:1	c.2657A>G	p.Asn886Ser	missense	Exon 9 of 23	ENSP00000264037.2	O75443
	TECTA	ENST00000642222.1		c.2657A>G	p.Asn886Ser	missense	Exon 10 of 24	ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000475 AC: 119 AN: 250476 AF XY: 0.000436

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.000821

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000836 AC: 1221 AN: 1460664 Hom.: 1 Cov.: 31 AF XY: 0.000807 AC XY: 586 AN XY: 726478

African (AFR) AF: 0.000120 AC: 4 AN: 33470

American (AMR) AF: 0.000515 AC: 23 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86126

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000997 AC: 1108 AN: 1111178

Other (OTH) AF: 0.00103 AC: 62 AN: 60358

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74470

African (AFR) AF: 0.000313 AC: 13 AN: 41556

American (AMR) AF: 0.000654 AC: 10 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000760 Hom.: 0

Bravo AF: 0.000525

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.000709

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	-	Autosomal recessive nonsyndromic hearing loss 21 (2)
-	1	-	Autosomal dominant nonsyndromic hearing loss 12 (1)
-	1	-	Autosomal dominant nonsyndromic hearing loss 12;C1863655:Autosomal recessive nonsyndromic hearing loss 21 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.23
Sift	Benign	0.23	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.74
MPC		0.85
ClinPred		0.080	T
GERP RS		5.7
PromoterAI		-0.015	Neutral
Varity_R		0.13
gMVP		0.59
Mutation Taster		=52/48	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: rs146175803; hg19: chr11-121000636; COSMIC: COSV50713002; COSMIC: COSV50713002;