rs10798333

Positions:

• chr1-175123571-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022093.2(TNN):​c.2822C>T​(p.Thr941Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,816 control chromosomes in the GnomAD database, including 132,464 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (11793 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120671 hom.)
• Consequence: TNN NM_022093.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126

Genes affected

TNN (HGNC:22942): (tenascin N) Predicted to enable integrin binding activity. Predicted to be involved in several processes, including generation of neurons; negative regulation of canonical Wnt signaling pathway involved in osteoblast differentiation; and negative regulation of osteoblast differentiation. Predicted to act upstream of or within axonogenesis. Predicted to be located in extracellular matrix and neuron projection. Predicted to be active in collagen-containing extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012792051).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNN	NM_022093.2	c.2822C>T	p.Thr941Met	missense_variant	12/19	ENST00000239462.9	NP_071376.1
TNN	XM_017002048.2	c.2876C>T	p.Thr959Met	missense_variant	12/19		XP_016857537.1
TNN	XM_017002049.2	c.2612C>T	p.Thr871Met	missense_variant	11/18		XP_016857538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNN	ENST00000239462.9	c.2822C>T	p.Thr941Met	missense_variant	12/19	2	NM_022093.2	ENSP00000239462	P1
TNN	ENST00000621086.1	c.2291C>T	p.Thr764Met	missense_variant	9/16	5		ENSP00000480895

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58711 AN: 151866 Hom.: 11785 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.0882

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.366

GnomAD3 exomes AF: 0.337 AC: 84767 AN: 251392 Hom.: 16115 AF XY: 0.337 AC XY: 45845 AN XY: 135872

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.0862

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.363

GnomAD4 exome AF: 0.397 AC: 580440 AN: 1461832 Hom.: 120671 Cov.: 80 AF XY: 0.392 AC XY: 285063 AN XY: 727216

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.0891

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.452

Gnomad4 NFE exome AF: 0.430

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.387 AC: 58751 AN: 151984 Hom.: 11793 Cov.: 32 AF XY: 0.382 AC XY: 28405 AN XY: 74298

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.0882

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.367

Alfa AF: 0.406 Hom.: 6058

Bravo AF: 0.373

TwinsUK AF: 0.458 AC: 1697

ALSPAC AF: 0.423 AC: 1631

ESP6500AA AF: 0.403 AC: 1776

ESP6500EA AF: 0.418 AC: 3593

ExAC AF: 0.343 AC: 41616

Asia WGS AF: 0.204 AC: 709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	0.99	P
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D;.;.
REVEL	Benign	0.14
Sift	Benign	0.034	D;.;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.54	P;.;.
Vest4		0.13
MPC		0.12
ClinPred		0.048	T
GERP RS		3.1
Varity_R		0.087
gMVP		0.28

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: rs10798333; hg19: chr1-175092707; COSMIC: COSV53431636;