chrX-644647-A-AGCCCCCCGCGC

Variant names:

• chrX-644647-A-AGCCCCCCGCGC
• rs886038300
• NM_000451.4:c.*16_*26dupCCCGCGCGCCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000451.4(SHOX):​c.*16_*26dupCCCGCGCGCCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,452,950 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 89 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., 44 hem., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom. 45 hem.)
• Consequence: SHOX NM_000451.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.631
• 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.

• BP6: Variant X-644647-A-AGCCCCCCGCGC is Benign according to our data. Variant chrX-644647-A-AGCCCCCCGCGC is described in ClinVar as Likely_benign. ClinVar VariationId is 256191.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000591 (90/152174) while in subpopulation AFR AF = 0.00207 (86/41516). AF 95% confidence interval is 0.00172. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 44 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	NM_000451.4	MANE Select	c.*16_*26dupCCCGCGCGCCC		3_prime_UTR	Exon 5 of 5	NP_000442.1
	SHOX	NM_006883.2		c.633+3565_633+3575dupCCCGCGCGCCC		intron	N/A	NP_006874.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOX	ENST00000686671.1	MANE Select	c.*16_*26dupCCCGCGCGCCC		3_prime_UTR	Exon 5 of 5	ENSP00000508521.1
	SHOX	ENST00000381575.6	TSL:1	c.633+3565_633+3575dupCCCGCGCGCCC		intron	N/A	ENSP00000370987.1
	SHOX	ENST00000381578.6	TSL:5	c.*16_*26dupCCCGCGCGCCC		3_prime_UTR	Exon 6 of 6	ENSP00000370990.1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152066 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000478

GnomAD2 exomes AF: 0.0000324 AC: 2 AN: 61806 AF XY: 0.0000281

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.00

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: 0.0000707 AC: 92 AN: 1300776 Hom.: 0 Cov.: 31 AF XY: 0.0000704 AC XY: 45 AN XY: 639442

African (AFR) AF: 0.00166 AC: 43 AN: 25914

American (AMR) AF: 0.0000911 AC: 2 AN: 21950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21670

East Asian (EAS) AF: 0.00 AC: 0 AN: 28966

South Asian (SAS) AF: 0.00 AC: 0 AN: 68512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3786

European-Non Finnish (NFE) AF: 0.0000393 AC: 41 AN: 1043546

Other (OTH) AF: 0.000111 AC: 6 AN: 53896

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74396

African (AFR) AF: 0.00207 AC: 86 AN: 41516

American (AMR) AF: 0.000196 AC: 3 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Bravo AF: 0.000669

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886038300; hg19: chrX-605382;