NM_001163678.2:c.14C>A

Variant names:

• chr3-158106011-G-T
• rs1713904347
• NM_001163678.2:c.14C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001163678.2(SHOX2):​c.14C>A​(p.Thr5Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOX2	NM_001163678.2	c.14C>A	p.Thr5Lys	missense_variant	Exon 1 of 5	ENST00000483851.7	NP_001157150.1
SHOX2	NM_003030.4	c.14C>A	p.Thr5Lys	missense_variant	Exon 1 of 6		NP_003021.3
SHOX2	NM_006884.3	c.14C>A	p.Thr5Lys	missense_variant	Exon 1 of 5		NP_006875.2
SHOX2	XM_006713727.4	c.14C>A	p.Thr5Lys	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.14C>A	p.Thr5Lys	missense_variant	Exon 1 of 5	2	NM_001163678.2	ENSP00000419362.1
SHOX2	ENST00000389589.8	c.14C>A	p.Thr5Lys	missense_variant	Exon 1 of 6	1		ENSP00000374240.4
SHOX2	ENST00000441443.6	c.14C>A	p.Thr5Lys	missense_variant	Exon 1 of 5	5		ENSP00000397099.3
RSRC1	ENST00000480820.5	c.-3+1G>T		splice_donor_variant, intron_variant	Intron 1 of 9	5		ENSP00000420150.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14C>A (p.T5K) alteration is located in exon 1 (coding exon 1) of the SHOX2 gene. This alteration results from a C to A substitution at nucleotide position 14, causing the threonine (T) at amino acid position 5 to be replaced by a lysine (K). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L;L;L
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.4	.;N;N
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.050	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.78
MutPred		0.34		Gain of ubiquitination at T5 (P = 0.0085);Gain of ubiquitination at T5 (P = 0.0085);Gain of ubiquitination at T5 (P = 0.0085);
MVP		0.98
MPC		1.7
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.072	Neutral
Varity_R		0.67
gMVP		0.86
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1713904347; hg19: chr3-157823800;