NM_000451.4:c.547G>C

Variant names:

• chrX-641001-G-C
• NM_000451.4:c.547G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000451.4(SHOX):​c.547G>C​(p.Val183Leu) 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 1 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom. 1 hem.)
• Consequence: SHOX NM_000451.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25964427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4	c.547G>C	p.Val183Leu	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.547G>C	p.Val183Leu	missense_variant, splice_region_variant	Exon 5 of 6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.547G>C	p.Val183Leu	missense_variant, splice_region_variant	Exon 4 of 5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.547G>C	p.Val183Leu	missense_variant, splice_region_variant	Exon 4 of 5	1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.547G>C	p.Val183Leu	missense_variant, splice_region_variant	Exon 5 of 6	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.547G>C	p.Val183Leu	missense_variant, splice_region_variant	Exon 5 of 6	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461564 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 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: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Langer mesomelic dysplasia syndrome Uncertain:1

Apr 13, 2023

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A homozygous missense variant in exon 5 of the SHOX gene that results in the amino acid substitution of Leucine for Valine at codon 183 (p.Val183Leu) was detected. The variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.024	T;.;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.16	B;B;B
Vest4		0.27
MutPred		0.38		Loss of methylation at K181 (P = 0.0741);Loss of methylation at K181 (P = 0.0741);Loss of methylation at K181 (P = 0.0741);
MVP		0.79
MPC		0.73
ClinPred		0.82	D
GERP RS		1.5
Varity_R		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-601736;