3-158105897-C-T

Variant names:

• chr3-158105897-C-T
• rs747138119
• NM_001163678.2:c.128G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001163678.2(SHOX2):​c.128G>A​(p.Cys43Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19636843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2	c.128G>A	p.Cys43Tyr	missense_variant	Exon 1 of 5	ENST00000483851.7	NP_001157150.1
SHOX2	NM_003030.4	c.128G>A	p.Cys43Tyr	missense_variant	Exon 1 of 6		NP_003021.3
SHOX2	NM_006884.3	c.128G>A	p.Cys43Tyr	missense_variant	Exon 1 of 5		NP_006875.2
SHOX2	XM_006713727.4	c.128G>A	p.Cys43Tyr	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.128G>A	p.Cys43Tyr	missense_variant	Exon 1 of 5	2	NM_001163678.2	ENSP00000419362.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432146 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 712442

African (AFR) AF: 0.00 AC: 0 AN: 30304

American (AMR) AF: 0.00 AC: 0 AN: 41892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25200

East Asian (EAS) AF: 0.00 AC: 0 AN: 35162

South Asian (SAS) AF: 0.00 AC: 0 AN: 84314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099188

Other (OTH) AF: 0.00 AC: 0 AN: 59030

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.128G>A (p.C43Y) alteration is located in exon 1 (coding exon 1) of the SHOX2 gene. This alteration results from a G to A substitution at nucleotide position 128, causing the cysteine (C) at amino acid position 43 to be replaced by a tyrosine (Y). 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	0.11
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.56	T;T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.0	N;N;N
PhyloP100		2.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.8	.;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.090	.;T;T
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.0	B;B;D
Vest4		0.20
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		0.61
MPC		0.95
ClinPred		0.31	T
GERP RS		3.9
PromoterAI		0.035	Neutral
Varity_R		0.30
gMVP		0.44
Mutation Taster		=77/23	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: rs747138119; hg19: chr3-157823686;