rs12532

Variant names:

• chr4-4863419-A-G
• rs12532
• NM_002448.3:c.*276A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002448.3(MSX1):​c.*276A>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 0.341 in 457,632 control chromosomes in the GnomAD database, including 28,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10750 hom., cov: 28)
  • Exomes 𝑓: 0.33 (18066 hom.)
• Consequence: MSX1 NM_002448.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.07
• Publications: 40 publications found

Genes affected

MSX1 (HGNC:7391): (msh homeobox 1) This gene encodes a member of the muscle segment homeobox gene family. The encoded protein functions as a transcriptional repressor during embryogenesis through interactions with components of the core transcription complex and other homeoproteins. It may also have roles in limb-pattern formation, craniofacial development, particularly odontogenesis, and tumor growth inhibition. Mutations in this gene, which was once known as homeobox 7, have been associated with nonsyndromic cleft lip with or without cleft palate 5, Witkop syndrome, Wolf-Hirschom syndrome, and autosomoal dominant hypodontia. [provided by RefSeq, Jul 2008]

MSX1 Gene-Disease associations (from GenCC):

• orofacial cleft 5

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• tooth agenesis, selective, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tooth and nail syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000308455 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-4863419-A-G is Benign according to our data. Variant chr4-4863419-A-G is described in ClinVar as Benign. ClinVar VariationId is 530788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3	c.*276A>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000382723.5	NP_002439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSX1	ENST00000382723.5	c.*276A>G		3_prime_UTR_variant	Exon 2 of 2	1	NM_002448.3	ENSP00000372170.4
ENSG00000308455	ENST00000834195.1	n.303+5389T>C		intron_variant	Intron 2 of 2
ENSG00000308455	ENST00000834196.1	n.48+4244T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 54985 AN: 151446 Hom.: 10724 Cov.: 28

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.343

GnomAD4 exome AF: 0.329 AC: 100810 AN: 306068 Hom.: 18066 Cov.: 0 AF XY: 0.325 AC XY: 52071 AN XY: 160186

African (AFR) AF: 0.447 AC: 3935 AN: 8808

American (AMR) AF: 0.495 AC: 5359 AN: 10818

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 2188 AN: 9836

East Asian (EAS) AF: 0.602 AC: 12559 AN: 20858

South Asian (SAS) AF: 0.275 AC: 9037 AN: 32886

European-Finnish (FIN) AF: 0.387 AC: 7087 AN: 18328

Middle Eastern (MID) AF: 0.285 AC: 400 AN: 1402

European-Non Finnish (NFE) AF: 0.293 AC: 54274 AN: 184924

Other (OTH) AF: 0.328 AC: 5971 AN: 18208

GnomAD4 genome AF: 0.363 AC: 55071 AN: 151564 Hom.: 10750 Cov.: 28 AF XY: 0.370 AC XY: 27397 AN XY: 74032

African (AFR) AF: 0.439 AC: 18143 AN: 41294

American (AMR) AF: 0.461 AC: 7039 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 751 AN: 3468

East Asian (EAS) AF: 0.607 AC: 3118 AN: 5136

South Asian (SAS) AF: 0.289 AC: 1390 AN: 4802

European-Finnish (FIN) AF: 0.379 AC: 3968 AN: 10476

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19648 AN: 67840

Other (OTH) AF: 0.349 AC: 729 AN: 2088

Alfa AF: 0.330 Hom.: 7659

Bravo AF: 0.373

Asia WGS AF: 0.436 AC: 1515 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23549991, 23231047, 24603642) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypoplastic enamel-onycholysis-hypohidrosis syndrome Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.78
PhyloP100		-1.1
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: rs12532; hg19: chr4-4865146;