X-641001-G-T

Position:

• chrX-641001-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000451.4(SHOX):​c.547G>T​(p.Val183Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom. 2 hem.)
• Consequence: SHOX NM_000451.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.70

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31376165).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHOX	NM_000451.4	c.547G>T	p.Val183Phe	missense_variant, splice_region_variant	4/5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.547G>T	p.Val183Phe	missense_variant, splice_region_variant	5/6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.547G>T	p.Val183Phe	missense_variant, splice_region_variant	4/5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.547G>T	p.Val183Phe	missense_variant, splice_region_variant	4/5	1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.547G>T	p.Val183Phe	missense_variant, splice_region_variant	5/6	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.547G>T	p.Val183Phe	missense_variant, splice_region_variant	5/6	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251158 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461564 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T;.;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.13	T;D;D
Sift4G	Benign	0.38	T;D;D
Polyphen		0.58	P;P;P
Vest4		0.21
MutPred		0.39		Loss of MoRF binding (P = 0.0881);Loss of MoRF binding (P = 0.0881);Loss of MoRF binding (P = 0.0881);
MVP		0.85
MPC		1.7
ClinPred		0.98	D
GERP RS		1.5
Varity_R		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs752189039; hg19: chrX-601736;