NM_002448.3:c.470-127C>A

Variant names:

• chr4-4862574-C-A
• rs33946149
• NM_002448.3:c.470-127C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002448.3(MSX1):​c.470-127C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,127,074 control chromosomes in the GnomAD database, including 12,626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1601 hom., cov: 34)
  • Exomes 𝑓: 0.15 (11025 hom.)
• Consequence: MSX1 NM_002448.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.364
• Publications: 4 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.047).
• BP6: Variant 4-4862574-C-A is Benign according to our data. Variant chr4-4862574-C-A is described in ClinVar as Benign. ClinVar VariationId is 1250675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 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.470-127C>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.470-127C>A		intron	N/A	ENSP00000372170.4
	MSX1	ENST00000468421.1	TSL:3	n.147C>A		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000308455	ENST00000834195.1		n.304-5785G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21666 AN: 152198 Hom.: 1602 Cov.: 34

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.0516

Gnomad SAS AF: 0.0972

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.134 AC: 30277 AN: 225572 AF XY: 0.135

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0890

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.0465

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.146 AC: 141966 AN: 974758 Hom.: 11025 Cov.: 14 AF XY: 0.145 AC XY: 73078 AN XY: 505508

African (AFR) AF: 0.118 AC: 2890 AN: 24446

American (AMR) AF: 0.0922 AC: 4059 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4206 AN: 23284

East Asian (EAS) AF: 0.0593 AC: 2227 AN: 37540

South Asian (SAS) AF: 0.101 AC: 7704 AN: 76216

European-Finnish (FIN) AF: 0.207 AC: 7860 AN: 37964

Middle Eastern (MID) AF: 0.165 AC: 800 AN: 4858

European-Non Finnish (NFE) AF: 0.155 AC: 105793 AN: 681670

Other (OTH) AF: 0.144 AC: 6427 AN: 44756

GnomAD4 genome AF: 0.142 AC: 21676 AN: 152316 Hom.: 1601 Cov.: 34 AF XY: 0.143 AC XY: 10648 AN XY: 74476

African (AFR) AF: 0.122 AC: 5061 AN: 41562

American (AMR) AF: 0.115 AC: 1754 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 656 AN: 3470

East Asian (EAS) AF: 0.0515 AC: 267 AN: 5184

South Asian (SAS) AF: 0.0963 AC: 465 AN: 4830

European-Finnish (FIN) AF: 0.211 AC: 2241 AN: 10614

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10819 AN: 68024

Other (OTH) AF: 0.130 AC: 276 AN: 2116

Alfa AF: 0.116 Hom.: 255

Bravo AF: 0.134

Asia WGS AF: 0.0820 AC: 287 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.41
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs33946149; hg19: chr4-4864301; COSMIC: COSV66947126;