rs193072890

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The ENST00000381575.6(SHOX):c.653G>A(p.Arg218His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 375,812 control chromosomes in the GnomAD database, including 27 homozygotes. There are 927 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 21 hom., 807 hem., cov: 28)

Exomes 𝑓: 0.0010 ( 6 hom. 120 hem. )

Consequence

SHOX
ENST00000381575.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.627

Publications

0 publications found

Variant links:

Genes affected

SHOX (HGNC:10853): (SHOX homeobox) This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

SHOX Gene-Disease associations (from GenCC):

Leri-Weill dyschondrosteosis
Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Langer mesomelic dysplasia
Inheritance: Unknown, XL, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
SHOX-related short stature
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SHOX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.53811 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, SHOX-related short stature.

BP4

Computational evidence support a benign effect (MetaRNN=0.003453523).

BP6

Variant X-658804-G-A is Benign according to our data. Variant chrX-658804-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448376.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1608/134346) while in subpopulation AFR AF = 0.042 (1473/35088). AF 95% confidence interval is 0.0402. There are 21 homozygotes in GnomAd4. There are 807 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 XL,Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_006883.2 link	c.653G>A	p.Arg218His	missense_variant	Exon 6 of 6		NP_006874.1	O15266-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000381575.6 link	c.653G>A	p.Arg218His	missense_variant	Exon 5 of 5	1		ENSP00000370987.1		O15266-2
SHOX	ENST00000334060.8 link	c.653G>A	p.Arg218His	missense_variant	Exon 6 of 6	5		ENSP00000335505.3		O15266-2

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1607

AN:

134240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0421

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00549

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000474

Gnomad FIN

AF:

0.000257

Gnomad MID

AF:

0.0156

Gnomad NFE

AF:

0.000593

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00129

AC:

125

AN:

97022

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.0207

Gnomad AMR exome

AF:

0.00213

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00201

GnomAD4 exome

AF:

0.00104

AC:

252

AN:

241466

Hom.:

Cov.:

AF XY:

0.000856

AC XY:

120

AN XY:

140114

show subpopulations

African (AFR)

AF:

0.0263

AC:

135

AN:

5128

American (AMR)

AF:

0.00205

AC:

AN:

22910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9188

East Asian (EAS)

AF:

0.00

AC:

AN:

5806

South Asian (SAS)

AF:

0.000330

AC:

AN:

48472

European-Finnish (FIN)

AF:

0.000186

AC:

AN:

10772

Middle Eastern (MID)

AF:

0.00118

AC:

AN:

844

European-Non Finnish (NFE)

AF:

0.000243

AC:

AN:

127392

Other (OTH)

AF:

0.00183

AC:

AN:

10954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0120

AC:

1608

AN:

134346

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

807

AN XY:

64514

show subpopulations

African (AFR)

AF:

0.0420

AC:

1473

AN:

35088

American (AMR)

AF:

0.00548

AC:

AN:

12582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3352

East Asian (EAS)

AF:

0.00

AC:

AN:

4384

South Asian (SAS)

AF:

0.000476

AC:

AN:

4206

European-Finnish (FIN)

AF:

0.000257

AC:

AN:

7788

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.000609

AC:

AN:

64050

Other (OTH)

AF:

0.0114

AC:

AN:

1850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

153

229

306

382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Bravo

AF:

0.0134

ExAC

AF:

0.000781

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SHOX: BS1, BS2 -

Aug 17, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SHOX-related disorder

Benign:1

Feb 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.72

(source)

DANN

Benign

0.82

FATHMM_MKL

Benign

0.00047

LIST_S2

Benign

0.30

T;.

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.38

PhyloP100

-0.63

PROVEAN

Benign

0.33

N;N

REVEL

Benign

0.14

Sift

Benign

0.13

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0

B;B

Vest4

0.070

MVP

0.53

ClinPred

0.0032

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over