chr4-4862018-C-A

Variant names:

• chr4-4862018-C-A
• rs3775261
• NM_002448.3:c.470-683C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002448.3(MSX1):​c.470-683C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 151,892 control chromosomes in the GnomAD database, including 7,609 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7609 hom., cov: 33)
• Consequence: MSX1 NM_002448.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.41
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002448.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	NM_002448.3	MANE Select	c.470-683C>A		intron	N/A	NP_002439.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	ENST00000382723.5	TSL:1 MANE Select	c.470-683C>A		intron	N/A	ENSP00000372170.4
	ENSG00000308455	ENST00000834195.1		n.304-5229G>T		intron	N/A
	ENSG00000308455	ENST00000834196.1		n.49-5229G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45926 AN: 151774 Hom.: 7595 Cov.: 33

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.289

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.303 AC: 45977 AN: 151892 Hom.: 7609 Cov.: 33 AF XY: 0.311 AC XY: 23117 AN XY: 74226

African (AFR) AF: 0.260 AC: 10766 AN: 41460

American (AMR) AF: 0.433 AC: 6619 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 735 AN: 3468

East Asian (EAS) AF: 0.600 AC: 3068 AN: 5116

South Asian (SAS) AF: 0.278 AC: 1338 AN: 4806

European-Finnish (FIN) AF: 0.367 AC: 3869 AN: 10556

Middle Eastern (MID) AF: 0.229 AC: 67 AN: 292

European-Non Finnish (NFE) AF: 0.275 AC: 18700 AN: 67888

Other (OTH) AF: 0.294 AC: 623 AN: 2116

Alfa AF: 0.287 Hom.: 7221

Bravo AF: 0.306

Asia WGS AF: 0.409 AC: 1419 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.098
DANN	Benign	0.62
PhyloP100		-2.4
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: rs3775261; hg19: chr4-4863745;