9-115073620-C-T

Position:

• chr9-115073620-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002160.4(TNC):​c.3197G>A​(p.Arg1066His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,578 control chromosomes in the GnomAD database, including 17,186 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1066C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1495 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15691 hom.)
• Consequence: TNC NM_002160.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.658

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]

LOC124902256 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014590621).
• BP6: Variant 9-115073620-C-T is Benign according to our data. Variant chr9-115073620-C-T is described in ClinVar as [Benign]. Clinvar id is 1287376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNC	NM_002160.4	c.3197G>A	p.Arg1066His	missense_variant	10/28	ENST00000350763.9
LOC124902256	XR_007061747.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNC	ENST00000350763.9	c.3197G>A	p.Arg1066His	missense_variant	10/28	1	NM_002160.4	P1
DELEC1	ENST00000649121.1	n.79-10635C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20649 AN: 152004 Hom.: 1494 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.0884

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.0625

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.122 AC: 30360 AN: 249366 Hom.: 2197 AF XY: 0.123 AC XY: 16610 AN XY: 134886

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0536

Gnomad ASJ exome AF: 0.0552

Gnomad EAS exome AF: 0.0677

Gnomad SAS exome AF: 0.117

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.142 AC: 207994 AN: 1461456 Hom.: 15691 Cov.: 32 AF XY: 0.142 AC XY: 103229 AN XY: 726966

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0562

Gnomad4 ASJ exome AF: 0.0586

Gnomad4 EAS exome AF: 0.0449

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.136 AC: 20659 AN: 152122 Hom.: 1495 Cov.: 32 AF XY: 0.133 AC XY: 9916 AN XY: 74338

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0883

Gnomad4 ASJ AF: 0.0695

Gnomad4 EAS AF: 0.0624

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.114

Alfa AF: 0.136 Hom.: 2430

Bravo AF: 0.129

TwinsUK AF: 0.143 AC: 529

ALSPAC AF: 0.157 AC: 604

ESP6500AA AF: 0.128 AC: 566

ESP6500EA AF: 0.145 AC: 1243

ExAC AF: 0.126 AC: 15334

Asia WGS AF: 0.0960 AC: 331 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.85
DEOGEN2	Benign	0.32	.;T;.;T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	T;T;T;T;T;.
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;.;.;L;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.13	T;T;T;T;T;T
Sift4G	Uncertain	0.042	D;D;D;D;D;D
Polyphen		0.0010, 0.025	.;B;.;B;.;.
Vest4		0.087
MPC		0.20
ClinPred		0.0095	T
GERP RS		3.0
Varity_R		0.074
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs1138545; hg19: chr9-117835899; COSMIC: COSV60785681;