ENST00000381578.6:c.-432-3C>A

Variant names:

• chrX-630463-C-A
• rs1030279647
• ENST00000381578.6:c.-432-3C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The ENST00000381578.6(SHOX):​c.-432-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 248,344 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 14 hem., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom. 4 hem.)
• Consequence: SHOX ENST00000381578.6 splice_region, intron
• Scores: Splicing: ADA: 0.05143
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: -0.983
• 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 -4 ACMG points.

• PP5: Variant X-630463-C-A is Pathogenic according to our data. Variant chrX-630463-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1683250.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd4 at 14 XL,Unknown,AR,AD gene

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.-432-3C>A		splice_region intron	N/A	NP_006874.1	O15266-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000381578.6	TSL:5	c.-432-3C>A		splice_region intron	N/A	ENSP00000370990.1	O15266-1
	SHOX	ENST00000334060.8	TSL:5	c.-432-3C>A		splice_region intron	N/A	ENSP00000335505.3	O15266-2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000104 AC: 10 AN: 96154 Hom.: 0 Cov.: 0 AF XY: 0.0000799 AC XY: 4 AN XY: 50048

African (AFR) AF: 0.00 AC: 0 AN: 3000

American (AMR) AF: 0.00 AC: 0 AN: 4070

Ashkenazi Jewish (ASJ) AF: 0.00171 AC: 4 AN: 2342

East Asian (EAS) AF: 0.00 AC: 0 AN: 4488

South Asian (SAS) AF: 0.00 AC: 0 AN: 12854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 324

European-Non Finnish (NFE) AF: 0.0000502 AC: 3 AN: 59720

Other (OTH) AF: 0.000601 AC: 3 AN: 4988

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74340

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Bravo AF: 0.000185

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Leri-Weill dyschondrosteosis (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.0070
DANN	Benign	0.51
PhyloP100		-0.98
PromoterAI		0.024	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.051
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.59		Position offset: 3

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

Other links and lift over

dbSNP: rs1030279647; hg19: chrX-591198;