X-634834-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000451.4(SHOX):​c.486+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000321 in 1,555,706 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 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: 𝑓 0.000020 ( 0 hom., 3 hem., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. 0 hem. )

Consequence

SHOX
NM_000451.4 splice_region, intron

Scores

2
Splicing: ADA: 0.00004498
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0950

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BS2
High Hemizygotes in GnomAd4 at 3 XL,Unknown,AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHOXNM_000451.4 linkc.486+8C>A splice_region_variant, intron_variant Intron 2 of 4 ENST00000686671.1 NP_000442.1 O15266-1A0A024R385
SHOXNM_006883.2 linkc.486+8C>A splice_region_variant, intron_variant Intron 3 of 5 NP_006874.1 O15266-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHOXENST00000686671.1 linkc.486+8C>A splice_region_variant, intron_variant Intron 2 of 4 NM_000451.4 ENSP00000508521.1 O15266-1
SHOXENST00000381575.6 linkc.486+8C>A splice_region_variant, intron_variant Intron 2 of 4 1 ENSP00000370987.1 O15266-2
SHOXENST00000381578.6 linkc.486+8C>A splice_region_variant, intron_variant Intron 3 of 5 5 ENSP00000370990.1 O15266-1
SHOXENST00000334060.8 linkc.486+8C>A splice_region_variant, intron_variant Intron 3 of 5 5 ENSP00000335505.3 O15266-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152122
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000633
AC:
1
AN:
157946
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000399
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:
0.00000142
AC:
2
AN:
1403584
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
692826
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31902
American (AMR)
AF:
0.0000552
AC:
2
AN:
36210
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25214
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36240
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80088
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48524
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4976
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1082324
Other (OTH)
AF:
0.00
AC:
0
AN:
58106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152122
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74306
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41436
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68004
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Bravo
AF:
0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
CADD
Benign
0.85
DANN
Benign
0.57
PhyloP100
-0.095

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000045
dbscSNV1_RF
Benign
0.0
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

Other links and lift over

dbSNP: rs374705909; hg19: chrX-595569; API