X-630463-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_006883.2(SHOX):c.-432-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 248,344 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 14 hem., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. 4 hem. )

Consequence

SHOX
NM_006883.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.05143

Clinical Significance

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

Conservation

PhyloP100: -0.983

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant X-630463-C-A is Pathogenic according to our data. Variant chrX-630463-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1683250.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chrX-630463-C-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).. Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAd at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_006883.2 linkuse as main transcript	c.-432-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000334060.8 linkuse as main transcript	c.-432-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5			O15266-2
SHOX	ENST00000381578.6 linkuse as main transcript	c.-432-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		P1	O15266-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74340

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.000104

AC:

AN:

96154

Hom.:

Cov.:

AF XY:

0.0000799

AC XY:

AN XY:

50048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00171

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000502

Gnomad4 OTH exome

AF:

0.000601

GnomAD4 genome

AF:

0.000171

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000955

Bravo

AF:

0.000185

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leri-Weill dyschondrosteosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 26, 2022

Variant summary: SHOX c.-432-3C>A alters a non-conserved nucleotide located close to a canonical splice site at the intron 1 and exon 2 boundary, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant weakens the 3' acceptor site. At least one publication reported experimental evidence, demonstrating in a minigene assay that the variant abolished normal splicing (Danzig_2012); however, authors of the study also noted that the SHOX gene might have an alternative promoter within exon 2, which should be unaffected by this splice acceptor site mutation in intron 1, which could generate a transcript and a fully functional Shox protein. The SHOX gene is located in the pseudoautosomal region of the X and Y chromosomes, and the variant allele was found at a frequency of 0.00017 in 150962 control chromosomes (gnomAD v3.1, genomes dataset), predominantly within the Ashkenazi Jewish subpopulation at a frequency of 0.0063 (i.e. 22/3468 alleles, all heterozygotes). The variant, c.-432-3C>A, has been reported in the literature in multiple heterozygous carriers who were affected with Short Stature (Danzig_2012, Shapiro_2015), and in one homozygous individual, who was affected with a more extreme short stature than his heterozygous children, but lacked features of Langer mesomelic dysplasia, suggesting that even if the variant affects splicing in vivo, some functional Shox protein was still produced (Danzig_2012). Since the expressivity of SHOX deficiency is highly variable (PMID: 21325865), these data indicate that the variant in heterozygous- or in homozygous state maybe associated with Short Stature, but it is unclear if it could contribute to more severe phenotypes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic for Short Stature phenotype. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

Cadd

Benign

0.0070

Dann

Benign

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.051

dbscSNV1_RF

Benign

0.32

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.59

Position offset: 3

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