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Y-630879-G-A

Position:

• chrY-630879-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The ENST00000711141.1(SHOX):​c.-19G>A variant causes a 5 prime UTR 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov:)
• Consequence: SHOX ENST00000711141.1 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.186

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_1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant Y-630879-G-A is Pathogenic according to our data. Variant chrY-630879-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 933226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (Cadd=8.291). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOX_1	NM_000451.4_1	c.-19G>A		5_prime_UTR_variant	1/5
SHOX_1	NM_006883.2_1	c.-19G>A		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000711142.1	c.-19G>A		5_prime_UTR_variant	1/5			ENSP00000518640.1
SHOX	ENST00000711141.1	c.-19G>A		5_prime_UTR_variant	1/5	1		ENSP00000518639.1
SHOX	ENST00000711145.1	c.-19G>A		5_prime_UTR_variant	2/6	5		ENSP00000518642.1
SHOX	ENST00000711143.1	c.-19G>A		5_prime_UTR_variant	2/6	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.

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leri-Weill dyschondrosteosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

SHOX-related short stature Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing;in vitro

Laboratory of Human Genetics, UPO, University of Eastern Piedmont

Jan 02, 2019

c.-19G>A variant in SHOX has been reported in 3 Italian individuals with idiopathic short stature. This variant was absent in large population studies. Additionally, in vitro functional studies indicated that this variant create an alternative branch site within exon 2 causing an aberrant mRNA splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CADD	Benign	8.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201157428; hg19: chrY-541614;