4-4859937-G-T

Variant names:

• chr4-4859937-G-T
• rs1448405080
• NM_002448.3:c.38G>T

Variant summary

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

The NM_002448.3(MSX1):​c.38G>T​(p.Gly13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSX1 NM_002448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• Publications: 1 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.38G>T	p.Gly13Val	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.38G>T	p.Gly13Val	missense	Exon 1 of 2	ENSP00000372170.4	P28360
	ENSG00000308455	ENST00000834195.1		n.304-3148C>A		intron	N/A
	ENSG00000308455	ENST00000834196.1		n.49-3148C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1344822 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 663452

African (AFR) AF: 0.00 AC: 0 AN: 27146

American (AMR) AF: 0.00 AC: 0 AN: 28724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30078

South Asian (SAS) AF: 0.00 AC: 0 AN: 73050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3986

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055914

Other (OTH) AF: 0.00 AC: 0 AN: 55228

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67936

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.056	T
Vest4		0.19
MVP		0.98
MPC		2.0
ClinPred		0.97	D
GERP RS		4.6
PromoterAI		-0.047	Neutral
Varity_R		0.35
gMVP		0.69
Mutation Taster		=83/17	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: rs1448405080; hg19: chr4-4861664;