X-631191-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000451.4(SHOX):c.277+17T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.974 in 1,612,446 control chromosomes in the GnomAD database, including 764,790 homozygotes. There are 779,154 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71631 hom., 72226 hem., cov: 34)
  • Exomes 𝑓: 0.97 (693159 hom. 706928 hem.)
• Consequence: SHOX NM_000451.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.909

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-631191-T-G is Benign according to our data. Variant chrX-631191-T-G is described in ClinVar as [Benign]. Clinvar id is 93092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-631191-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX	NM_000451.4	c.277+17T>G		intron_variant		ENST00000686671.1
SHOX	NM_006883.2	c.277+17T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX	ENST00000686671.1	c.277+17T>G		intron_variant			NM_000451.4	P1
SHOX	ENST00000381575.6	c.277+17T>G		intron_variant		1
SHOX	ENST00000334060.8	c.277+17T>G		intron_variant		5
SHOX	ENST00000381578.6	c.277+17T>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147558 AN: 152152 Hom.: 71581 Cov.: 34 AF XY: 0.970 AC XY: 72103 AN XY: 74304

Gnomad AFR AF: 0.960

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.975

Gnomad ASJ AF: 0.921

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.989

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.977

Gnomad OTH AF: 0.973

GnomAD3 exomes AF: 0.970 AC: 241076 AN: 248660 Hom.: 116951 AF XY: 0.969 AC XY: 130940 AN XY: 135190

Gnomad AFR exome AF: 0.958

Gnomad AMR exome AF: 0.986

Gnomad ASJ exome AF: 0.917

Gnomad EAS exome AF: 0.947

Gnomad SAS exome AF: 0.952

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.976

Gnomad OTH exome AF: 0.966

GnomAD4 exome AF: 0.974 AC: 1422506 AN: 1460176 Hom.: 693159 Cov.: 58 AF XY: 0.973 AC XY: 706928 AN XY: 726360

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.986

Gnomad4 ASJ exome AF: 0.921

Gnomad4 EAS exome AF: 0.949

Gnomad4 SAS exome AF: 0.951

Gnomad4 FIN exome AF: 0.987

Gnomad4 NFE exome AF: 0.978

Gnomad4 OTH exome AF: 0.970

GnomAD4 genome AF: 0.970 AC: 147667 AN: 152270 Hom.: 71631 Cov.: 34 AF XY: 0.970 AC XY: 72226 AN XY: 74432

Gnomad4 AFR AF: 0.960

Gnomad4 AMR AF: 0.975

Gnomad4 ASJ AF: 0.921

Gnomad4 EAS AF: 0.948

Gnomad4 SAS AF: 0.953

Gnomad4 FIN AF: 0.989

Gnomad4 NFE AF: 0.976

Gnomad4 OTH AF: 0.974

Bravo AF: 0.969

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.6
Dann	Benign	0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs2239402; hg19: chrX-591926;