chr9-115040947-T-A

Variant names:

• chr9-115040947-T-A
• rs431905513
• NM_002160.4:c.5386A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_002160.4(TNC):​c.5386A>T​(p.Thr1796Ser) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNC NM_002160.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.28
• Publications: 5 publications found

Genes affected

TNC (HGNC:5318): (tenascin C) This gene encodes an extracellular matrix protein with a spatially and temporally restricted tissue distribution. This protein is homohexameric with disulfide-linked subunits, and contains multiple EGF-like and fibronectin type-III domains. It is implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity, and neuronal regeneration. [provided by RefSeq, Jul 2011]

DELEC1 (HGNC:23658): (deleted in esophageal cancer 1) The function of this gene is not known. This gene is located in a region commonly deleted in esophageal squamous cell carcinomas. Gene expression is reduced or absent in these carcinomas and thus this is a candidate tumor suppressor gene for esophageal squamous cell carcinomas. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-115040947-T-A is Pathogenic according to our data. Variant chr9-115040947-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 97009.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28140616). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002160.4. 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
	TNC	NM_002160.4	MANE Select	c.5386A>T	p.Thr1796Ser	missense	Exon 19 of 28	NP_002151.2
	TNC	NM_001439065.1		c.5935A>T	p.Thr1979Ser	missense	Exon 21 of 30	NP_001425994.1
	TNC	NM_001439066.1		c.5935A>T	p.Thr1979Ser	missense	Exon 22 of 31	NP_001425995.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNC	ENST00000350763.9	TSL:1 MANE Select	c.5386A>T	p.Thr1796Ser	missense	Exon 19 of 28	ENSP00000265131.4
	TNC	ENST00000423613.6	TSL:1	c.4567A>T	p.Thr1523Ser	missense	Exon 16 of 25	ENSP00000411406.2
	TNC	ENST00000542877.6	TSL:1	c.4297A>T	p.Thr1433Ser	missense	Exon 15 of 24	ENSP00000442242.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 56 Pathogenic:1

Jul 30, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.55
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.3
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.12
Sift	Benign	0.037	D
Sift4G	Benign	0.27	T
Polyphen		0.15	B
Vest4		0.48
MutPred		0.26		Gain of disorder (P = 0.0348)
MVP		0.48
MPC		0.14
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.25
gMVP		0.40
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs431905513; hg19: chr9-117803226;