Variant 3-158105730-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001163678.2(SHOX2):c.295A>T(p.Met99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,524,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SHOX2
NM_001163678.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.66

Variant links:

Genes affected

SHOX2 (HGNC:10854): (SHOX homeobox 2) This gene is a member of the homeobox family of genes that encode proteins containing a 60-amino acid residue motif that represents a DNA binding domain. Homeobox genes have been characterized extensively as transcriptional regulators involved in pattern formation in both invertebrate and vertebrate species. Several human genetic disorders are caused by aberrations in human homeobox genes. This locus represents a pseudoautosomal homeobox gene that is thought to be responsible for idiopathic short stature, and it is implicated in the short stature phenotype of Turner syndrome patients. This gene is considered to be a candidate gene for Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

SHOX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10684472).

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SHOX2	NM_001163678.2 linkuse as main transcript	c.295A>T	p.Met99Leu	missense_variant	1/5	ENST00000483851.7
SHOX2	NM_003030.4 linkuse as main transcript	c.295A>T	p.Met99Leu	missense_variant	1/6
SHOX2	NM_006884.3 linkuse as main transcript	c.295A>T	p.Met99Leu	missense_variant	1/5
SHOX2	XM_006713727.4 linkuse as main transcript	c.295A>T	p.Met99Leu	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX2	ENST00000483851.7 linkuse as main transcript	c.295A>T	p.Met99Leu	missense_variant	1/5	2	NM_001163678.2	P4	O60902-2
SHOX2	ENST00000389589.8 linkuse as main transcript	c.295A>T	p.Met99Leu	missense_variant	1/6	1			O60902-3
SHOX2	ENST00000441443.6 linkuse as main transcript	c.295A>T	p.Met99Leu	missense_variant	1/5	5		A1	O60902-1
SHOX2	ENST00000554685.2 linkuse as main transcript			upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

151942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000236

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000117

AC:

AN:

119674

Hom.:

AF XY:

0.000137

AC XY:

AN XY:

65932

show subpopulations

Gnomad AFR exome

AF:

0.000266

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000464

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000262

Gnomad OTH exome

AF:

0.000301

GnomAD4 exome

AF:

0.000129

AC:

177

AN:

1372812

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

677708

show subpopulations

Gnomad4 AFR exome

AF:

0.0000694

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000115

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.000140

GnomAD4 genome

AF:

0.000118

AC:

AN:

151942

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000236

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000260

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.63

T;T;T

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.42

N;N;N

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.72

.;N;N

REVEL

Benign

0.075

Sift

Benign

0.52

.;T;T

Sift4G

Benign

0.32

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.55

MutPred

0.33

Loss of catalytic residue at M99 (P = 0.0221);Loss of catalytic residue at M99 (P = 0.0221);Loss of catalytic residue at M99 (P = 0.0221);

MVP

0.48

MPC

0.53

ClinPred

0.068

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.32

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