chrX-630463-C-A

Variant names:

• chrX-630463-C-A
• rs1030279647
• ENST00000381578.6:c.-432-3C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_006883.2(SHOX):​c.-432-3C>A variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.05143
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: -0.983

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]

ACMG classification

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=2, 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 GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_006883.2	c.-432-3C>A		splice_region_variant, intron_variant	Intron 1 of 5		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000381578.6	c.-432-3C>A		splice_region_variant, intron_variant	Intron 1 of 5	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.-432-3C>A		splice_region_variant, intron_variant	Intron 1 of 5	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74340

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: 10 AN: 96154 Hom.: 0 Cov.: 0 AF XY: 0.0000799 AC XY: 4 AN XY: 50048

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: 26 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74340

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:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leri-Weill dyschondrosteosis Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Aug 28, 2024

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 (NM_000451.4) c.-435C>A is located in the untranscribed region upstream of the SHOX gene region. However, this variant alters a non-conserved nucleotide located close to a canonical splice site c.-432-3C>A at the intron 1 and exon 2 boundary in a alternate transcript (NM_006883.2). Therefore, it 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 a 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 0.00015 in 246,792 control chromosomes (36/246,792 alleles, all heterozygotes), predominantly at a frequency of 0.0045 within the Ashkenazi Jewish subpopulation in the gnomAD database (v4.0 dataset). The variant, described as 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 with 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. The following publications have been ascertained in the context of this evaluation (PMID: 23426818, 25659810, 34627339). ClinVar contains an entry for this variant (Variation ID: 1683250). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic for Short Stature phenotype. -

not provided Uncertain:1

Mar 25, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 23426818) -

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

Other links and lift over

dbSNP: rs1030279647; hg19: chrX-591198;