X-630879-G-C

Variant names:

• chrX-630879-G-C
• rs201157428
• NM_000451.4:c.-19G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000451.4(SHOX):​c.-19G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,612,316 control chromosomes in the GnomAD database, including 8 homozygotes. There are 230 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., 124 hem., cov: 33)
  • Exomes 𝑓: 0.00017 (3 hom. 106 hem.)
• Consequence: SHOX NM_000451.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.520
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-630879-G-C is Benign according to our data. Variant chrX-630879-G-C is described in ClinVar as Benign. ClinVar VariationId is 448372.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00187 (284/152264) while in subpopulation AFR AF = 0.00647 (269/41568). AF 95% confidence interval is 0.00584. There are 5 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 XL,Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX	NM_000451.4	c.-19G>C		5_prime_UTR_variant	Exon 1 of 5	ENST00000686671.1	NP_000442.1
SHOX	NM_006883.2	c.-19G>C		5_prime_UTR_variant	Exon 2 of 6		NP_006874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX	ENST00000686671.1	c.-19G>C		5_prime_UTR_variant	Exon 1 of 5		NM_000451.4	ENSP00000508521.1
SHOX	ENST00000381575.6	c.-19G>C		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000370987.1
SHOX	ENST00000381578.6	c.-19G>C		5_prime_UTR_variant	Exon 2 of 6	5		ENSP00000370990.1
SHOX	ENST00000334060.8	c.-19G>C		5_prime_UTR_variant	Exon 2 of 6	5		ENSP00000335505.3

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152146 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000506 AC: 126 AN: 248958 AF XY: 0.000318

Gnomad AFR exome AF: 0.00723

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000168 AC: 246 AN: 1460052 Hom.: 3 Cov.: 30 AF XY: 0.000146 AC XY: 106 AN XY: 726258

African (AFR) AF: 0.00634 AC: 212 AN: 33454

American (AMR) AF: 0.000313 AC: 14 AN: 44708

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5334

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111710

Other (OTH) AF: 0.000265 AC: 16 AN: 60294

GnomAD4 genome AF: 0.00187 AC: 284 AN: 152264 Hom.: 5 Cov.: 33 AF XY: 0.00167 AC XY: 124 AN XY: 74456

African (AFR) AF: 0.00647 AC: 269 AN: 41568

American (AMR) AF: 0.000784 AC: 12 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Bravo AF: 0.00212

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 28, 2016

Athena Diagnostics

Significance: 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	-0.86
CADD	Benign	7.2
DANN	Benign	0.39
PhyloP100		0.52
PromoterAI		-0.061	Neutral

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: rs201157428; hg19: chrX-591614;