Genetic Variant SHOX:p.Ala233Val (chrX-644455-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000451.4(SHOX):c.698C>T(p.Ala233Val) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,522,312 control chromosomes in the GnomAD database, including 1 homozygotes. There are 98 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 14 hem., cov: 33)

Exomes 𝑓: 0.00013 ( 1 hom. 84 hem. )

Consequence

SHOX
NM_000451.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 4.40

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):

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

SHOX links:

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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=0.0122663975).

BP6

Variant X-644455-C-T is Benign according to our data. Variant chrX-644455-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448377.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000118 (18/152266) while in subpopulation EAS AF = 0.00348 (18/5166). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 14 XL,Unknown,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000451.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	NM_000451.4	MANE Select	c.698C>T	p.Ala233Val	missense	Exon 5 of 5	NP_000442.1	O15266-1
	SHOX	NM_006883.2		c.633+3368C>T		intron	N/A	NP_006874.1	O15266-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHOX	ENST00000686671.1	MANE Select	c.698C>T	p.Ala233Val	missense	Exon 5 of 5	ENSP00000508521.1	O15266-1
SHOX	ENST00000381575.6	TSL:1	c.633+3368C>T		intron	N/A	ENSP00000370987.1	O15266-2
SHOX	ENST00000381578.6	TSL:5	c.698C>T	p.Ala233Val	missense	Exon 6 of 6	ENSP00000370990.1	O15266-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152158

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:

0.00367

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000273

AC:

AN:

120878

AF XY:

0.000271

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000126

AC:

173

AN:

1370046

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

676288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28784

American (AMR)

AF:

0.00

AC:

AN:

35036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24540

East Asian (EAS)

AF:

0.00474

AC:

160

AN:

33768

South Asian (SAS)

AF:

0.0000387

AC:

AN:

77452

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4262

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

1074406

Other (OTH)

AF:

0.000122

AC:

AN:

57170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000118

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00348

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Bravo

AF:

0.000291

ExAC

AF:

0.000149

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

SHOX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.6

PhyloP100

4.4

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.64

Sift

Benign

0.16

Sift4G

Benign

0.36

Polyphen

1.0

Vest4

0.35

MutPred

0.54

Loss of disorder (P = 0.052)

MVP

0.99

MPC

1.5

ClinPred

0.20

GERP RS

1.7

Varity_R

0.23

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over