3-158105910-C-T

Variant names:

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

Variant summary

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

The NM_001163678.2(SHOX2):​c.115G>A​(p.Glu39Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,690 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E39Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3058716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2	c.115G>A	p.Glu39Lys	missense_variant	Exon 1 of 5	ENST00000483851.7	NP_001157150.1
SHOX2	NM_003030.4	c.115G>A	p.Glu39Lys	missense_variant	Exon 1 of 6		NP_003021.3
SHOX2	NM_006884.3	c.115G>A	p.Glu39Lys	missense_variant	Exon 1 of 5		NP_006875.2
SHOX2	XM_006713727.4	c.115G>A	p.Glu39Lys	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>A	p.Glu39Lys	missense_variant	Exon 1 of 5	2	NM_001163678.2	ENSP00000419362.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450690 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 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: 0.0000116 AC: 1 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: 9.03e-7 AC: 1 AN: 1107200

Other (OTH) AF: 0.00 AC: 0 AN: 59888

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	0.026
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	T;D;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.3	L;L;L
PhyloP100		2.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.17	.;N;N
REVEL	Benign	0.22
Sift	Benign	0.064	.;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.99	D;P;D
Vest4		0.26
MutPred		0.26		Gain of ubiquitination at E39 (P = 0.0077);Gain of ubiquitination at E39 (P = 0.0077);Gain of ubiquitination at E39 (P = 0.0077);
MVP		0.59
MPC		0.66
ClinPred		0.84	D
GERP RS		3.5
PromoterAI		0.0025	Neutral
Varity_R		0.22
gMVP		0.46
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;