11-121189859-G-C

Variant names:

• chr11-121189859-G-C
• rs372023989
• NM_005422.4:c.6346G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005422.4(TECTA):​c.6346G>C​(p.Glu2116Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2116D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34
• Publications: 0 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]

ENSG00000299284 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11466041).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECTA	NM_005422.4	MANE Select	c.6346G>C	p.Glu2116Gln	missense	Exon 23 of 24	NP_005413.2
	TBCEL-TECTA	NM_001378761.1		c.7288G>C	p.Glu2430Gln	missense	Exon 29 of 30	NP_001365690.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECTA	ENST00000392793.6	TSL:5 MANE Select	c.6346G>C	p.Glu2116Gln	missense	Exon 23 of 24	ENSP00000376543.1
	TECTA	ENST00000264037.2	TSL:1	c.6346G>C	p.Glu2116Gln	missense	Exon 22 of 23	ENSP00000264037.2
	TECTA	ENST00000642222.1		c.6331G>C	p.Glu2111Gln	missense	Exon 23 of 24	ENSP00000493855.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Glu2116Gln vari ant in TECTA has not been previously reported in individuals with hearing loss o r in large population studies. The glutamic acid (Glu) at position 2116 is not c onserved in mammals or evolutionary distant species, raising the possibility tha t a change at this position may be tolerated. Additional computational predicti on tools suggest that the Glu2116Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary , while the clinical significance of the Glu2116Gln variant is uncertain, these data suggest that it is more likely to be benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.0089	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.19
Sift	Benign	0.14	T
Sift4G	Benign	0.41	T
Polyphen		0.037	B
Vest4		0.22
MutPred		0.19		Loss of sheet (P = 0.0817)
MVP		0.80
MPC		0.33
ClinPred		0.32	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.38
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs372023989; hg19: chr11-121060568;