rs778186580

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000451.4(SHOX):c.-9delG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000624 in 1,612,664 control chromosomes in the GnomAD database, including 2 homozygotes. There are 517 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 23 hem., cov: 33)

Exomes 𝑓: 0.00065 ( 2 hom. 494 hem. )

Consequence

SHOX
NM_000451.4 5_prime_UTR

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 2.25

Publications

1 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 -9 ACMG points.

BP6

Variant X-630887-CG-C is Benign according to our data. Variant chrX-630887-CG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586583.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000394 (60/152172) while in subpopulation NFE AF = 0.000794 (54/68032). AF 95% confidence interval is 0.000625. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 23 XL,Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4 link	c.-9delG		5_prime_UTR_variant	Exon 1 of 5	ENST00000686671.1	NP_000442.1	O15266-1A0A024R385
SHOX	NM_006883.2 link	c.-9delG		5_prime_UTR_variant	Exon 2 of 6		NP_006874.1	O15266-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHOX	ENST00000686671.1 link	c.-9delG	5_prime_UTR_variant	Exon 1 of 5		NM_000451.4	ENSP00000508521.1	O15266-1
SHOX	ENST00000381575.6 link	c.-9delG	5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000370987.1	O15266-2
SHOX	ENST00000381578.6 link	c.-9delG	5_prime_UTR_variant	Exon 2 of 6	5		ENSP00000370990.1	O15266-1
SHOX	ENST00000334060.8 link	c.-9delG	5_prime_UTR_variant	Exon 2 of 6	5		ENSP00000335505.3	O15266-2

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000437

AC:

109

AN:

249470

AF XY:

0.000443

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 FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000953

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000648

AC:

946

AN:

1460492

Hom.:

Cov.:

AF XY:

0.000680

AC XY:

494

AN XY:

726518

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0000380

AC:

AN:

52598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.000828

AC:

921

AN:

1111782

Other (OTH)

AF:

0.000348

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Jun 26, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SHOX c.-9delG is located in the untranslated mRNA region upstream of the initiation codon. This frequency is not significantly higher than estimated for a pathogenic variant in SHOX causing Langer Mesomelic Dysplasia (0.00044 vs 0.0022), allowing no conclusion about variant significance. c.-9delG has been observed in individuals affected with clinical features of SHOX-related disorders (Hirschfeldova_2017, Babu_2021, Toni_2023). These reports do not provide unequivocal conclusions about association of the variant with Langer Mesomelic Dysplasia. At least one publication reports experimental evidence evaluating an impact on protein function and this variant might interfere with the correct SHOX expression (Babu_2021). The following publications have been ascertained in the context of this evaluation (PMID: 32647378, 27708272, 37019085). ClinVar contains an entry for this variant (Variation ID: 586583). Based on the evidence outlined above, the variant was classified as uncertain significance. -

May 24, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=293/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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