5-174730708-A-G

Position:

• chr5-174730708-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002449.5(MSX2):​c.*1125A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 152,454 control chromosomes in the GnomAD database, including 46,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.77 (46667 hom., cov: 32)
  • Exomes 𝑓: 0.83 (151 hom.)
• Consequence: MSX2 NM_002449.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.28

Genes affected

MSX2 (HGNC:7392): (msh homeobox 2) This gene encodes a member of the muscle segment homeobox gene family. The encoded protein is a transcriptional repressor whose normal activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. The encoded protein may also have a role in promoting cell growth under certain conditions and may be an important target for the RAS signaling pathways. Mutations in this gene are associated with parietal foramina 1 and craniosynostosis type 2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 5-174730708-A-G is Benign according to our data. Variant chr5-174730708-A-G is described in ClinVar as [Benign]. Clinvar id is 352862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSX2	NM_002449.5	c.*1125A>G		3_prime_UTR_variant	2/2	ENST00000239243.7	NP_002440.2
MSX2	NM_001363626.2	c.*1553A>G		3_prime_UTR_variant	2/2		NP_001350555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSX2	ENST00000239243.7	c.*1125A>G		3_prime_UTR_variant	2/2	1	NM_002449.5	ENSP00000239243	P1

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116696 AN: 151900 Hom.: 46658 Cov.: 32

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.850

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.894

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.844

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.788

GnomAD4 exome AF: 0.828 AC: 361 AN: 436 Hom.: 151 Cov.: 0 AF XY: 0.840 AC XY: 220 AN XY: 262

Gnomad4 FIN exome AF: 0.827

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.833

GnomAD4 genome AF: 0.768 AC: 116747 AN: 152018 Hom.: 46667 Cov.: 32 AF XY: 0.773 AC XY: 57429 AN XY: 74332

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.851

Gnomad4 ASJ AF: 0.837

Gnomad4 EAS AF: 0.983

Gnomad4 SAS AF: 0.895

Gnomad4 FIN AF: 0.846

Gnomad4 NFE AF: 0.857

Gnomad4 OTH AF: 0.782

Alfa AF: 0.847 Hom.: 85381

Bravo AF: 0.757

Asia WGS AF: 0.883 AC: 3071 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Craniosynostosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Parietal foramina 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.81

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: rs14459; hg19: chr5-174157711;