10-101131896-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_005521.4(TLX1):c.355A>G(p.Ser119Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,395,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

TLX1
NM_005521.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.79

Variant links:

Genes affected

TLX1 (HGNC:5056): (T cell leukemia homeobox 1) This gene encodes a nuclear transcription factor that belongs to the NK-linked or NK-like (NKL) subfamily of homeobox genes. The encoded protein is required for normal development of the spleen during embryogenesis. This protein is also involved in specification of neuronal cell fates. Ectopic expression of this gene due to chromosomal translocations is associated with certain T-cell acute lymphoblastic leukemias. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2010]

TLX1 links:

TLX1NB (HGNC:37183): (TLX1 neighbor)

TLX1NB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08600694).

BP6

Variant 10-101131896-A-G is Benign according to our data. Variant chr10-101131896-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2383636.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLX1	NM_005521.4 link	c.355A>G	p.Ser119Gly	missense_variant	Exon 1 of 3	ENST00000370196.11	NP_005512.1	P31314-1
TLX1	NM_001195517.2 link	c.355A>G	p.Ser119Gly	missense_variant	Exon 1 of 3		NP_001182446.1	P31314-2
TLX1	XM_011539744.4 link	c.355A>G	p.Ser119Gly	missense_variant	Exon 1 of 3		XP_011538046.1
TLX1NB	NR_130724.1 link	n.580-4798T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX1	ENST00000370196.11 link	c.355A>G	p.Ser119Gly	missense_variant	Exon 1 of 3	1	NM_005521.4	ENSP00000359215.6		P31314-1

Frequencies

GnomAD3 genomes

AF:

0.000520

AC:

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00253

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00

AC:

AN:

25840

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000973

AC:

121

AN:

1243168

Hom.:

Cov.:

AF XY:

0.0000987

AC XY:

AN XY:

607722

show subpopulations

African (AFR)

AF:

0.00184

AC:

AN:

24422

American (AMR)

AF:

0.000235

AC:

AN:

12784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18710

East Asian (EAS)

AF:

0.00180

AC:

AN:

27740

South Asian (SAS)

AF:

0.0000358

AC:

AN:

55944

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32132

Middle Eastern (MID)

AF:

0.000203

AC:

AN:

4930

European-Non Finnish (NFE)

AF:

0.00000887

AC:

AN:

1015170

Other (OTH)

AF:

0.000214

AC:

AN:

51336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000520

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00253

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67938

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000631

Asia WGS

AF:

0.00203

AC:

AN:

3462

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 28, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.21

T;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.35

T;T;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.086

T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

-1.1

N;N;.

PhyloP100

1.8

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.40

N;N;.

REVEL

Benign

0.25

Sift

Benign

0.39

T;T;.

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.13

MutPred

0.30

Loss of glycosylation at S119 (P = 0.0057);Loss of glycosylation at S119 (P = 0.0057);.;

MVP

0.72

ClinPred

0.035

GERP RS

3.0

PromoterAI

0.024

Neutral

(source)

Varity_R

0.077

gMVP

0.28

Mutation Taster

=95/5

polymorphism

(source)

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

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10-101131896-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over