X-630526-G-C

Variant names:

• chrX-630526-G-C
• rs2239401
• ENST00000381578.6:c.-372G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000381578.6(SHOX):​c.-372G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 243,718 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom. 1 hem.)
• Consequence: SHOX ENST00000381578.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0290
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Leri-Weill dyschondrosteosis

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Langer mesomelic dysplasia

  Inheritance: Unknown, XL, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• SHOX-related short stature

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381578.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	NM_006883.2		c.-372G>C		5_prime_UTR	Exon 2 of 6	NP_006874.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000381578.6	TSL:5	c.-372G>C		5_prime_UTR	Exon 2 of 6	ENSP00000370990.1
	SHOX	ENST00000334060.8	TSL:5	c.-372G>C		5_prime_UTR	Exon 2 of 6	ENSP00000335505.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000821 AC: 2 AN: 243718 Hom.: 0 Cov.: 0 AF XY: 0.00000784 AC XY: 1 AN XY: 127594

African (AFR) AF: 0.00 AC: 0 AN: 7598

American (AMR) AF: 0.000109 AC: 1 AN: 9152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7190

East Asian (EAS) AF: 0.00 AC: 0 AN: 13450

South Asian (SAS) AF: 0.00 AC: 0 AN: 32510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 146474

Other (OTH) AF: 0.0000739 AC: 1 AN: 13540

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.9
DANN	Benign	0.86
PhyloP100		-0.029
PromoterAI		0.087	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2239401; hg19: chrX-591261;