1-175079335-C-A

Position:

chr1-175079335-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022093.2(TNN):c.412C>A(p.Leu138Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,590,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

TNN
NM_022093.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.60

Variant links:

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]

TNN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056385756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNN	NM_022093.2 linkuse as main transcript	c.412C>A	p.Leu138Ile	missense_variant, splice_region_variant	3/19	ENST00000239462.9	NP_071376.1
TNN	XM_017002048.2 linkuse as main transcript	c.466C>A	p.Leu156Ile	missense_variant, splice_region_variant	3/19		XP_016857537.1
TNN	XM_017002049.2 linkuse as main transcript	c.466C>A	p.Leu156Ile	missense_variant, splice_region_variant	3/18		XP_016857538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNN	ENST00000239462.9 linkuse as main transcript	c.412C>A	p.Leu138Ile	missense_variant, splice_region_variant	3/19	2	NM_022093.2	ENSP00000239462	P1
TNN	ENST00000621086.1 linkuse as main transcript	c.412C>A	p.Leu138Ile	missense_variant, splice_region_variant	2/16	5		ENSP00000480895

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000499

AC:

AN:

220550

Hom.:

AF XY:

0.0000654

AC XY:

AN XY:

122350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000388

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000153

AC:

AN:

1437992

Hom.:

Cov.:

AF XY:

0.0000252

AC XY:

AN XY:

715494

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000261

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000834

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.412C>A (p.L138I) alteration is located in exon 3 (coding exon 2) of the TNN gene. This alteration results from a C to A substitution at nucleotide position 412, causing the leucine (L) at amino acid position 138 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.6

DANN

Benign

0.94

DEOGEN2

Benign

0.00058

T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.36

T;T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.45

N;.;.

REVEL

Benign

0.0040

Sift

Benign

0.28

T;.;.

Sift4G

Benign

0.29

T;T;T

Polyphen

0.041

B;.;.

Vest4

0.29

MutPred

0.26

Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);

MVP

0.33

MPC

0.10

ClinPred

0.033

GERP RS

0.087

Varity_R

0.038

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over