4-4860029-G-C

Variant names:

• chr4-4860029-G-C
• rs1737868931
• NM_002448.3:c.130G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002448.3(MSX1):​c.130G>C​(p.Gly44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,350 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G44S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: MSX1 NM_002448.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47
• Publications: 0 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, NO_KNOWN Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000308455 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	NM_002448.3	MANE Select	c.130G>C	p.Gly44Arg	missense	Exon 1 of 2	NP_002439.2	P28360

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	ENST00000382723.5	TSL:1 MANE Select	c.130G>C	p.Gly44Arg	missense	Exon 1 of 2	ENSP00000372170.4	P28360
	ENSG00000308455	ENST00000834195.1		n.304-3240C>G		intron	N/A
	ENSG00000308455	ENST00000834196.1		n.49-3240C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354350 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 667908

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27234

American (AMR) AF: 0.00 AC: 0 AN: 30028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23714

East Asian (EAS) AF: 0.00 AC: 0 AN: 31030

South Asian (SAS) AF: 0.00 AC: 0 AN: 74462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46742

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4924

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060348

Other (OTH) AF: 0.00 AC: 0 AN: 55868

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.018	D
Vest4		0.49
MVP		0.97
MPC		1.7
ClinPred		0.97	D
GERP RS		4.7
PromoterAI		-0.080	Neutral
Varity_R		0.19
gMVP		0.49
Mutation Taster		=79/21	polymorphism

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: rs1737868931; hg19: chr4-4861756;