3-158105910-C-G

Variant names:

• chr3-158105910-C-G
• rs772067593
• NM_001163678.2:c.115G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001163678.2(SHOX2):​c.115G>C​(p.Glu39Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,450,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89
• 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]

RSRC1 (HGNC:24152): (arginine and serine rich coiled-coil 1) This gene encodes a member of the serine and arginine rich-related protein family. The encoded protein is involved in both constitutive and alternative mRNA splicing. This gene may be associated with schizophrenia. A pseudogene of this gene is located on chromosome 9. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]

RSRC1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 70

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27449846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2	c.115G>C	p.Glu39Gln	missense_variant	Exon 1 of 5	ENST00000483851.7	NP_001157150.1
SHOX2	NM_003030.4	c.115G>C	p.Glu39Gln	missense_variant	Exon 1 of 6		NP_003021.3
SHOX2	NM_006884.3	c.115G>C	p.Glu39Gln	missense_variant	Exon 1 of 5		NP_006875.2
SHOX2	XM_006713727.4	c.115G>C	p.Glu39Gln	missense_variant	Exon 1 of 6		XP_006713790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOX2	ENST00000483851.7	c.115G>C	p.Glu39Gln	missense_variant	Exon 1 of 5	2	NM_001163678.2	ENSP00000419362.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000307 AC: 7 AN: 228126 AF XY: 0.0000475

Gnomad AFR exome AF: 0.00

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: 0.0000152 AC: 22 AN: 1450690 Hom.: 0 Cov.: 33 AF XY: 0.0000263 AC XY: 19 AN XY: 721726

African (AFR) AF: 0.00 AC: 0 AN: 32238

American (AMR) AF: 0.00 AC: 0 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 37930

South Asian (SAS) AF: 0.000244 AC: 21 AN: 85918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107200

Other (OTH) AF: 0.0000167 AC: 1 AN: 59888

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000335 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115G>C (p.E39Q) alteration is located in exon 1 (coding exon 1) of the SHOX2 gene. This alteration results from a G to C substitution at nucleotide position 115, causing the glutamic acid (E) at amino acid position 39 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.3	L;L;L
PhyloP100		2.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.51	.;N;N
REVEL	Benign	0.19
Sift	Benign	0.038	.;D;D
Sift4G	Benign	0.22	T;T;T
Polyphen		0.99	D;P;D
Vest4		0.30
MutPred		0.15		Loss of glycosylation at K38 (P = 0.0323);Loss of glycosylation at K38 (P = 0.0323);Loss of glycosylation at K38 (P = 0.0323);
MVP		0.64
MPC		1.0
ClinPred		0.65	D
GERP RS		3.5
PromoterAI		-0.00090	Neutral
Varity_R		0.20
gMVP		0.36
Mutation Taster		=157/143	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: rs772067593; hg19: chr3-157823699;