ENST00000381578:c.-649C>G

Variant names:

• chrX-624386-C-G
• rs886039879
• ENST00000381578.6:c.-649C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The ENST00000381578.6(SHOX):​c.-649C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000306 in 130,912 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. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency: Genomes: 𝑓 0.000031 (0 hom., 1 hem., cov: 22)
• Consequence: SHOX ENST00000381578.6 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.13
• 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):

• Langer mesomelic dysplasia

  Inheritance: AR, XL, Unknown Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• Leri-Weill dyschondrosteosis

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-624386-C-G is Benign according to our data. Variant chrX-624386-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 265992.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	NM_006883.2		c.-649C>G		5_prime_UTR	Exon 1 of 6	NP_006874.1	O15266-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000381578.6	TSL:5	c.-649C>G		5_prime_UTR	Exon 1 of 6	ENSP00000370990.1	O15266-1
	SHOX	ENST00000334060.8	TSL:5	c.-649C>G		5_prime_UTR	Exon 1 of 6	ENSP00000335505.3	O15266-2

Frequencies

GnomAD3 genomes AF: 0.0000306 AC: 4 AN: 130912 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000767

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000348

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000306 AC: 4 AN: 130912 Hom.: 0 Cov.: 22 AF XY: 0.0000158 AC XY: 1 AN XY: 63230

African (AFR) AF: 0.0000259 AC: 1 AN: 38642

American (AMR) AF: 0.0000767 AC: 1 AN: 13036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3058

East Asian (EAS) AF: 0.00 AC: 0 AN: 4556

South Asian (SAS) AF: 0.00 AC: 0 AN: 4316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000348 AC: 2 AN: 57466

Other (OTH) AF: 0.00 AC: 0 AN: 1740

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SHOX-related short stature (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.68
DANN	Benign	0.24
PhyloP100		-1.1
PromoterAI		0.016	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: rs886039879; hg19: chrX-585121;