X-644455-C-A

Variant names:

• chrX-644455-C-A
• rs750375727
• NM_000451.4:c.698C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000451.4(SHOX):​c.698C>A​(p.Ala233Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000073 in 1,370,048 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. A233V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom. 1 hem.)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	NM_000451.4	MANE Select	c.698C>A	p.Ala233Glu	missense	Exon 5 of 5	NP_000442.1
	SHOX	NM_006883.2		c.633+3368C>A		intron	N/A	NP_006874.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000686671.1	MANE Select	c.698C>A	p.Ala233Glu	missense	Exon 5 of 5	ENSP00000508521.1
	SHOX	ENST00000381575.6	TSL:1	c.633+3368C>A		intron	N/A	ENSP00000370987.1
	SHOX	ENST00000381578.6	TSL:5	c.698C>A	p.Ala233Glu	missense	Exon 6 of 6	ENSP00000370990.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000827 AC: 1 AN: 120878 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000428

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370048 Hom.: 0 Cov.: 32 AF XY: 0.00000148 AC XY: 1 AN XY: 676290

African (AFR) AF: 0.00 AC: 0 AN: 28784

American (AMR) AF: 0.00 AC: 0 AN: 35036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24540

East Asian (EAS) AF: 0.00 AC: 0 AN: 33770

South Asian (SAS) AF: 0.00 AC: 0 AN: 77452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4262

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074406

Other (OTH) AF: 0.0000175 AC: 1 AN: 57170

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.57
Sift	Benign	0.044	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.28
MutPred		0.27		Gain of catalytic residue at A233 (P = 0.0329)
MVP		0.94
MPC		1.7
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.59
Mutation Taster		=77/23	polymorphism

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: rs750375727; hg19: chrX-605190;