rs749355015

Variant names:

• chrX-644677-C-A
• rs749355015
• NM_000451.4:c.*41C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000451.4(SHOX):​c.*41C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,396,558 control chromosomes in the GnomAD database, including 15 homozygotes. There are 1,019 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (7 hom., 371 hem., cov: 33)
  • Exomes 𝑓: 0.0011 (8 hom. 648 hem.)
• Consequence: SHOX NM_000451.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.329
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0048 (731/152224) while in subpopulation AFR AF = 0.0147 (609/41518). AF 95% confidence interval is 0.0137. There are 7 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,XL,AD,Unknown gene

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.*41C>A		3_prime_UTR	Exon 5 of 5	NP_000442.1	O15266-1
	SHOX	NM_006883.2		c.633+3590C>A		intron	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.*41C>A		3_prime_UTR	Exon 5 of 5	ENSP00000508521.1	O15266-1
	SHOX	ENST00000381575.6	TSL:1	c.633+3590C>A		intron	N/A	ENSP00000370987.1	O15266-2
	SHOX	ENST00000381578.6	TSL:5	c.*41C>A		3_prime_UTR	Exon 6 of 6	ENSP00000370990.1	O15266-1

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 725 AN: 152112 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00182 AC: 24 AN: 13208 AF XY: 0.00230

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.00308

Gnomad ASJ exome AF: 0.00372

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000657

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00111 AC: 1376 AN: 1244334 Hom.: 8 Cov.: 31 AF XY: 0.00107 AC XY: 648 AN XY: 607386

African (AFR) AF: 0.0181 AC: 440 AN: 24284

American (AMR) AF: 0.00263 AC: 34 AN: 12904

Ashkenazi Jewish (ASJ) AF: 0.000686 AC: 12 AN: 17492

East Asian (EAS) AF: 0.0000352 AC: 1 AN: 28394

South Asian (SAS) AF: 0.000279 AC: 16 AN: 57430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30114

Middle Eastern (MID) AF: 0.00340 AC: 12 AN: 3526

European-Non Finnish (NFE) AF: 0.000719 AC: 732 AN: 1018780

Other (OTH) AF: 0.00251 AC: 129 AN: 51410

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152224 Hom.: 7 Cov.: 33 AF XY: 0.00499 AC XY: 371 AN XY: 74422

African (AFR) AF: 0.0147 AC: 609 AN: 41518

American (AMR) AF: 0.00412 AC: 63 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68000

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Bravo AF: 0.00553

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	SHOX-related short stature (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.1
DANN	Benign	0.42
PhyloP100		0.33

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: rs749355015; hg19: chrX-605412;