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chrY-630463-C-A

Variant names:

• chrY-630463-C-A
• rs1030279647
• ENST00000711145.1:c.-432-3C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The ENST00000711145.1(SHOX):​c.-432-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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: not found (cov:)
• Consequence: SHOX ENST00000711145.1 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: -1.65

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 Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant Y-630463-C-A is Pathogenic according to our data. Variant chrY-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}.
• BP4: Computational evidence support a benign effect (Cadd=0.006). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX_1	NM_006883.2_1	c.-432-3C>A		splice_region_variant, intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000711145.1	c.-432-3C>A		splice_region_variant, intron_variant	Intron 1 of 5	5		ENSP00000518642.1
SHOX	ENST00000711143.1	c.-432-3C>A		splice_region_variant, intron_variant	Intron 1 of 5	5		ENSP00000518641.1

Frequencies

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Alfa AF: 0.000285 Hom.: 0

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
CADD	Benign	0.0060

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1030279647; hg19: chrY-541198;