rs14459

Variant names:

• chr5-174730708-A-G
• rs14459
• NM_002449.5:c.*1125A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-174730708-A-G
• chr5-174730708-A-C
• chr5-174730708-A-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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]

MSX2 Gene-Disease associations (from GenCC):

• craniosynostosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet
• parietal foramina

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• parietal foramina with cleidocranial dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• parietal foramina 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002449.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX2	NM_002449.5	MANE Select	c.*1125A>G		3_prime_UTR	Exon 2 of 2	NP_002440.2
	MSX2	NM_001363626.2		c.*1553A>G		3_prime_UTR	Exon 2 of 2	NP_001350555.1	D6RIS4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX2	ENST00000239243.7	TSL:1 MANE Select	c.*1125A>G		3_prime_UTR	Exon 2 of 2	ENSP00000239243.5	P35548

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.827 AC: 354 AN: 428

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 0.833 AC: 5 AN: 6

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

African (AFR) AF: 0.522 AC: 21588 AN: 41386

American (AMR) AF: 0.851 AC: 13008 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2906 AN: 3472

East Asian (EAS) AF: 0.983 AC: 5094 AN: 5180

South Asian (SAS) AF: 0.895 AC: 4316 AN: 4824

European-Finnish (FIN) AF: 0.846 AC: 8922 AN: 10548

Middle Eastern (MID) AF: 0.849 AC: 248 AN: 292

European-Non Finnish (NFE) AF: 0.857 AC: 58297 AN: 68006

Other (OTH) AF: 0.782 AC: 1647 AN: 2106

Alfa AF: 0.825 Hom.: 140137

Bravo AF: 0.757

Asia WGS AF: 0.883 AC: 3071 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Craniosynostosis 2 (1)
-	-	1	Parietal foramina 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs14459; hg19: chr5-174157711;