rs12532

Positions:

• chr4-4863419-A-G

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: -1.07

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
MSX1	NM_002448.3	c.*276A>G		3_prime_UTR_variant	2/2	ENST00000382723.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX1	ENST00000382723.5	c.*276A>G		3_prime_UTR_variant	2/2	1	NM_002448.3	P1

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

Gnomad4 AFR exome AF: 0.447

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.602

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.328

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

Gnomad4 AFR AF: 0.439

Gnomad4 AMR AF: 0.461

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.349

Alfa AF: 0.306 Hom.: 4233

Bravo AF: 0.373

Asia WGS AF: 0.436 AC: 1515 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypoplastic enamel-onycholysis-hypohidrosis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.78

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: rs12532; hg19: chr4-4865146;