rs876658016

Variant names:

• chr11-121130022-C-G
• rs876658016
• NM_005422.4:c.2752C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-121130022-C-G
• chr11-121130022-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005422.4(TECTA):​c.2752C>G​(p.Pro918Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). The gene TECTA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

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.2752C>G	p.Pro918Ala	missense	Exon 10 of 24	NP_005413.2	O75443
	TBCEL-TECTA	NM_001378761.1		c.3709C>G	p.Pro1237Ala	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.2752C>G	p.Pro918Ala	missense	Exon 10 of 24	ENSP00000376543.1	O75443
	TECTA	ENST00000264037.2	TSL:1	c.2752C>G	p.Pro918Ala	missense	Exon 9 of 23	ENSP00000264037.2	O75443
	TECTA	ENST00000642222.1		c.2752C>G	p.Pro918Ala	missense	Exon 10 of 24	ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250036 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458882 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725148

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.0000449 AC: 2 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109920

Other (OTH) AF: 0.00 AC: 0 AN: 60226

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.0028	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.64
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.54		Gain of catalytic residue at P918 (P = 0.0366)
MVP		0.94
MPC		0.96
ClinPred		0.94	D
GERP RS		5.8
PromoterAI		0.069	Neutral
Varity_R		0.18
gMVP		0.73
Mutation Taster		=33/67	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: rs876658016; hg19: chr11-121000731;