3-158105895-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001163678.2(SHOX2):c.130A>G(p.Thr44Ala) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T44S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053012818).
• BP6: Variant 3-158105895-T-C is Benign according to our data. Variant chr3-158105895-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2534556.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX2	NM_001163678.2	c.130A>G	p.Thr44Ala	missense_variant	1/5	ENST00000483851.7
SHOX2	NM_003030.4	c.130A>G	p.Thr44Ala	missense_variant	1/6
SHOX2	NM_006884.3	c.130A>G	p.Thr44Ala	missense_variant	1/5
SHOX2	XM_006713727.4	c.130A>G	p.Thr44Ala	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX2	ENST00000483851.7	c.130A>G	p.Thr44Ala	missense_variant	1/5	2	NM_001163678.2	P4
SHOX2	ENST00000389589.8	c.130A>G	p.Thr44Ala	missense_variant	1/6	1
SHOX2	ENST00000441443.6	c.130A>G	p.Thr44Ala	missense_variant	1/5	5		A1
RSRC1	ENST00000480820.5	c.-118T>C		5_prime_UTR_variant	1/10	5		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	7.5
Dann	Benign	0.83
DEOGEN2	Benign	0.088	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.36	T;T;T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Pathogenic	0.82	D
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.049
MutPred		0.11		Gain of glycosylation at T41 (P = 0.0394);Gain of glycosylation at T41 (P = 0.0394);Gain of glycosylation at T41 (P = 0.0394);
MVP		0.49
MPC		0.55
ClinPred		0.056	T
GERP RS		-1.3
Varity_R		0.039
gMVP		0.17

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-157823684;