X-630983-A-C

Variant names:

• chrX-630983-A-C
• rs146304983
• NM_000451.4:c.86A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_000451.4(SHOX):​c.86A>C​(p.Lys29Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000833 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 648 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., 26 hem., cov: 33)
  • Exomes 𝑓: 0.00088 (0 hom. 622 hem.)
• Consequence: SHOX NM_000451.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.96
• 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 -10 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.53811 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Leri-Weill dyschondrosteosis, Langer mesomelic dysplasia, SHOX-related short stature.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14937094).
• BP6: Variant X-630983-A-C is Benign according to our data. Variant chrX-630983-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93095.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00042 (64/152256) while in subpopulation NFE AF = 0.000765 (52/68010). AF 95% confidence interval is 0.000599. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 26 XL,Unknown,AR,AD 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.86A>C	p.Lys29Thr	missense	Exon 1 of 5	NP_000442.1
	SHOX	NM_006883.2		c.86A>C	p.Lys29Thr	missense	Exon 2 of 6	NP_006874.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000686671.1	MANE Select	c.86A>C	p.Lys29Thr	missense	Exon 1 of 5	ENSP00000508521.1
	SHOX	ENST00000381575.6	TSL:1	c.86A>C	p.Lys29Thr	missense	Exon 1 of 5	ENSP00000370987.1
	SHOX	ENST00000381578.6	TSL:5	c.86A>C	p.Lys29Thr	missense	Exon 2 of 6	ENSP00000370990.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000765

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000454 AC: 114 AN: 250928 AF XY: 0.000494

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000865

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000876 AC: 1280 AN: 1461468 Hom.: 0 Cov.: 30 AF XY: 0.000856 AC XY: 622 AN XY: 727052

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.000269 AC: 12 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00110 AC: 1218 AN: 1111826

Other (OTH) AF: 0.000762 AC: 46 AN: 60376

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74454

African (AFR) AF: 0.000144 AC: 6 AN: 41556

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Bravo AF: 0.000495

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	2	not specified (2)
-	1	-	SHOX-related short stature (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.65
Sift	Benign	0.062	T
Sift4G	Benign	0.068	T
Polyphen		0.95	P
Vest4		0.31
MVP		0.98
MPC		0.71
ClinPred		0.053	T
GERP RS		1.9
PromoterAI		-0.17	Neutral
Varity_R		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146304983; hg19: chrX-591718;