X-634734-CTC-ATT

Variant names:

• chrX-634734-CTC-ATT
• NM_000451.4:c.394_396delCTCinsATT
• SHOX p.Leu132Ile

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP2

The NM_000451.4(SHOX):​c.394_396delCTCinsATT​(p.Leu132Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L132V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.55
• 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: AD, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Langer mesomelic dysplasia

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-634734-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9875.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.53811 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Langer mesomelic dysplasia, Leri-Weill dyschondrosteosis, SHOX-related short stature.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000451.4. 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_000451.4	MANE Select	c.394_396delCTCinsATT	p.Leu132Ile	missense	N/A	NP_000442.1	O15266-1
	SHOX	NM_006883.2		c.394_396delCTCinsATT	p.Leu132Ile	missense	N/A	NP_006874.1	O15266-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000686671.1	MANE Select	c.394_396delCTCinsATT	p.Leu132Ile	missense	N/A	ENSP00000508521.1	O15266-1
	SHOX	ENST00000381575.6	TSL:1	c.394_396delCTCinsATT	p.Leu132Ile	missense	N/A	ENSP00000370987.1	O15266-2
	SHOX	ENST00000381578.6	TSL:5	c.394_396delCTCinsATT	p.Leu132Ile	missense	N/A	ENSP00000370990.1	O15266-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-595469;