chr3-158098308-T-C

Variant names:

• chr3-158098308-T-C
• rs772063838
• ENST00000389589.8:c.787A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001163678.2(SHOX2):​c.703-24A>G variant causes a intron change. The variant allele was found at a frequency of 0.00000137 in 1,458,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SHOX2 NM_001163678.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08
• Publications: 0 publications found

Genes affected

SHOX2 (HGNC:10854): (SHOX homeobox 2) This gene is a member of the homeobox family of genes that encode proteins containing a 60-amino acid residue motif that represents a DNA binding domain. Homeobox genes have been characterized extensively as transcriptional regulators involved in pattern formation in both invertebrate and vertebrate species. Several human genetic disorders are caused by aberrations in human homeobox genes. This locus represents a pseudoautosomal homeobox gene that is thought to be responsible for idiopathic short stature, and it is implicated in the short stature phenotype of Turner syndrome patients. This gene is considered to be a candidate gene for Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

SHOX2 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (MetaRNN=0.28394645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2	c.703-24A>G		intron_variant	Intron 4 of 4	ENST00000483851.7	NP_001157150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX2	ENST00000389589.8	c.787A>G	p.Asn263Asp	missense_variant	Exon 6 of 6	1		ENSP00000374240.4
SHOX2	ENST00000483851.7	c.703-24A>G		intron_variant	Intron 4 of 4	2	NM_001163678.2	ENSP00000419362.1
SHOX2	ENST00000441443.6	c.715A>G	p.Asn239Asp	missense_variant	Exon 5 of 5	5		ENSP00000397099.3
SHOX2	ENST00000490689.3	n.1854-24A>G		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458504 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725188

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110152

Other (OTH) AF: 0.00 AC: 0 AN: 60246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	0.016
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.0	N;.
PhyloP100		4.1
PrimateAI	Pathogenic	0.83	D
REVEL	Uncertain	0.41
Sift4G	Benign	0.34	T;T
Polyphen		0.96	P;B
Vest4		0.59
MutPred		0.41		Gain of disorder (P = 0.19);.;
MVP		0.52
MPC		1.4
ClinPred		0.95	D
GERP RS		4.8
La Branchor		0.77
BranchPoint Hunter		3.0
Varity_R		0.44
gMVP		0.62
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs772063838; hg19: chr3-157816097;