9-115046506-T-A

Variant names:

• chr9-115046506-T-A
• rs2104772
• NM_002160.4:c.5029A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002160.4(TNC):​c.5029A>T​(p.Ile1677Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,613,834 control chromosomes in the GnomAD database, including 153,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17242 hom., cov: 32)
  • Exomes 𝑓: 0.43 (136268 hom.)
• Consequence: TNC NM_002160.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.850
• Publications: 71 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5833974E-4).
• BP6: Variant 9-115046506-T-A is Benign according to our data. Variant chr9-115046506-T-A is described in ClinVar as Benign. ClinVar VariationId is 1238979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

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.5029A>T	p.Ile1677Leu	missense	Exon 17 of 28	NP_002151.2
	TNC	NM_001439065.1		c.5578A>T	p.Ile1860Leu	missense	Exon 19 of 30	NP_001425994.1
	TNC	NM_001439066.1		c.5578A>T	p.Ile1860Leu	missense	Exon 20 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.5029A>T	p.Ile1677Leu	missense	Exon 17 of 28	ENSP00000265131.4
	TNC	ENST00000542877.6	TSL:1	c.3940A>T	p.Ile1314Leu	missense	Exon 13 of 24	ENSP00000442242.1
	TNC	ENST00000423613.6	TSL:1	c.4307-4165A>T		intron	N/A	ENSP00000411406.2

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71588 AN: 151890 Hom.: 17222 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.467

GnomAD2 exomes AF: 0.437 AC: 109906 AN: 251412 AF XY: 0.433

Gnomad AFR exome AF: 0.561

Gnomad AMR exome AF: 0.418

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.444

GnomAD4 exome AF: 0.430 AC: 628402 AN: 1461826 Hom.: 136268 Cov.: 58 AF XY: 0.429 AC XY: 312093 AN XY: 727214

African (AFR) AF: 0.560 AC: 18742 AN: 33474

American (AMR) AF: 0.425 AC: 18989 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 10804 AN: 26136

East Asian (EAS) AF: 0.450 AC: 17866 AN: 39700

South Asian (SAS) AF: 0.406 AC: 35028 AN: 86256

European-Finnish (FIN) AF: 0.470 AC: 25099 AN: 53418

Middle Eastern (MID) AF: 0.482 AC: 2780 AN: 5768

European-Non Finnish (NFE) AF: 0.425 AC: 472742 AN: 1111962

Other (OTH) AF: 0.436 AC: 26352 AN: 60394

GnomAD4 genome AF: 0.471 AC: 71644 AN: 152008 Hom.: 17242 Cov.: 32 AF XY: 0.472 AC XY: 35076 AN XY: 74304

African (AFR) AF: 0.560 AC: 23192 AN: 41434

American (AMR) AF: 0.441 AC: 6745 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1467 AN: 3472

East Asian (EAS) AF: 0.433 AC: 2237 AN: 5166

South Asian (SAS) AF: 0.400 AC: 1923 AN: 4810

European-Finnish (FIN) AF: 0.483 AC: 5101 AN: 10570

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.432 AC: 29362 AN: 67964

Other (OTH) AF: 0.466 AC: 982 AN: 2108

Alfa AF: 0.436 Hom.: 11283

Bravo AF: 0.474

TwinsUK AF: 0.407 AC: 1510

ALSPAC AF: 0.420 AC: 1619

ESP6500AA AF: 0.563 AC: 2482

ESP6500EA AF: 0.431 AC: 3705

ExAC AF: 0.438 AC: 53222

Asia WGS AF: 0.431 AC: 1504 AN: 3478

EpiCase AF: 0.436

EpiControl AF: 0.438

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16115819)

Autosomal dominant nonsyndromic hearing loss 56 Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.00016	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.85
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Benign	0.76	T
Polyphen		0.0040	B
Vest4		0.26
MutPred		0.44		Gain of disorder (P = 0.0919)
MPC		0.22
ClinPred		0.0071	T
GERP RS		3.4
Varity_R		0.19
gMVP		0.69
Mutation Taster		=94/6	polymorphism (auto)

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: rs2104772; hg19: chr9-117808785; COSMIC: COSV60782293; COSMIC: COSV60782293;