NM_000451.4:c.634-14G>T

Variant names:

• chrX-644377-G-T
• rs759067813
• NM_000451.4:c.634-14G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000451.4(SHOX):​c.634-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,518,042 control chromosomes in the GnomAD database, including 1 homozygotes. There are 90 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., 48 hem., cov: 33)
  • Exomes 𝑓: 0.000067 (1 hom. 42 hem.)
• Consequence: SHOX NM_000451.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.06
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-644377-G-T is Benign according to our data. Variant chrX-644377-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 448375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000742 (113/152190) while in subpopulation AFR AF = 0.00265 (110/41538). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 48 XL,Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4	c.634-14G>T		intron_variant	Intron 4 of 4	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.633+3290G>T		intron_variant	Intron 5 of 5		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.634-14G>T		intron_variant	Intron 4 of 4		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.633+3290G>T		intron_variant	Intron 4 of 4	1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.634-14G>T		intron_variant	Intron 5 of 5	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.633+3290G>T		intron_variant	Intron 5 of 5	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152074 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000951 AC: 11 AN: 115642 AF XY: 0.0000941

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.000222

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000666 AC: 91 AN: 1365852 Hom.: 1 Cov.: 32 AF XY: 0.0000623 AC XY: 42 AN XY: 673978

African (AFR) AF: 0.00229 AC: 66 AN: 28836

American (AMR) AF: 0.000175 AC: 6 AN: 34340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24438

East Asian (EAS) AF: 0.0000299 AC: 1 AN: 33474

South Asian (SAS) AF: 0.00 AC: 0 AN: 77128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4020

European-Non Finnish (NFE) AF: 0.00000653 AC: 7 AN: 1072516

Other (OTH) AF: 0.000193 AC: 11 AN: 57018

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74392

African (AFR) AF: 0.00265 AC: 110 AN: 41538

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Bravo AF: 0.000718

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 17, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SHOX c.634-14G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.5e-05 in 115642 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. This frequency is higher than the expected frequency for a pathogenic variant, supporting evidence that the variant is benign. c.634-14G>T has been reported in the literature in an individual affected with Leri-Weill Dyschondrosteosis without strong evidence for causality (Auger_2016). This report does not provide unequivocal conclusions about association of the variant with Leri-Weill Dyschondrosteosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Leri-Weill dyschondrosteosis;C0432230:Langer mesomelic dysplasia syndrome;C1845118:SHOX-related short stature Benign:1

Apr 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0030
DANN	Benign	0.70
PhyloP100		-2.1

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: rs759067813; hg19: chrX-605112;