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Y-630833-C-A

Variant names:

• chrY-630833-C-A
• rs922062046
• ENST00000711142.1:c.-65C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000711141.1(SHOX):​c.-65C>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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov:)
• Consequence: SHOX ENST00000711141.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.88

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.

• BP4: Computational evidence support a benign effect (Cadd=11.72).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX_1	NM_000451.4_1	c.-65C>A		5_prime_UTR_variant	Exon 1 of 5
SHOX_1	NM_006883.2_1	c.-65C>A		5_prime_UTR_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000711142.1	c.-65C>A		5_prime_UTR_variant	Exon 1 of 5			ENSP00000518640.1
SHOX	ENST00000711141.1	c.-65C>A		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000518639.1
SHOX	ENST00000711145.1	c.-65C>A		5_prime_UTR_variant	Exon 2 of 6	5		ENSP00000518642.1
SHOX	ENST00000711143.1	c.-65C>A		5_prime_UTR_variant	Exon 2 of 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: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2023

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: HOX c.-65C>A is located in the untranslated mRNA region upstream of the initiation codon. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.7e-05 in 1598724 control chromosomes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in SHOX causing Leri-Weill Dyschondrosteosis (2.7e-05 vs 0.00025), allowing no conclusion about variant significance. c.-65C>A has been reported in the literature in individuals affected with Leri-Weill Dyschondrosteosis or suspected skeletal dysplasia (Grigelioniene_2001, Scocchia_2021). These reports do not provide unequivocal conclusions about association of the variant with Leri-Weill Dyschondrosteosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11735031, 34627339). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

SHOX-related short stature Uncertain:1

Oct 07, 2020

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CADD	Benign	12

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs922062046; hg19: chrY-541568;