3-158105730-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001163678.2(SHOX2):c.295A>T(p.Met99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,524,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SHOX2 NM_001163678.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10684472).
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOX2	NM_001163678.2	c.295A>T	p.Met99Leu	missense_variant	1/5	ENST00000483851.7
SHOX2	NM_003030.4	c.295A>T	p.Met99Leu	missense_variant	1/6
SHOX2	NM_006884.3	c.295A>T	p.Met99Leu	missense_variant	1/5
SHOX2	XM_006713727.4	c.295A>T	p.Met99Leu	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOX2	ENST00000483851.7	c.295A>T	p.Met99Leu	missense_variant	1/5	2	NM_001163678.2	P4
SHOX2	ENST00000389589.8	c.295A>T	p.Met99Leu	missense_variant	1/6	1
SHOX2	ENST00000441443.6	c.295A>T	p.Met99Leu	missense_variant	1/5	5		A1
SHOX2	ENST00000554685.2			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151942 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000117 AC: 14 AN: 119674 Hom.: 0 AF XY: 0.000137 AC XY: 9 AN XY: 65932

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000464

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.000301

GnomAD4 exome AF: 0.000129 AC: 177 AN: 1372812 Hom.: 0 Cov.: 33 AF XY: 0.000124 AC XY: 84 AN XY: 677708

Gnomad4 AFR exome AF: 0.0000694

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000115

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.000140

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151942 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74248

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000236

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000260 AC: 2

ExAC AF: 0.000132 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.63	T;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.42	N;N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.93	D
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.55
MutPred		0.33		Loss of catalytic residue at M99 (P = 0.0221);Loss of catalytic residue at M99 (P = 0.0221);Loss of catalytic residue at M99 (P = 0.0221);
MVP		0.48
MPC		0.53
ClinPred		0.068	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs375389609; hg19: chr3-157823519;