chr4-4860357-C-T

Variant names:

• chr4-4860357-C-T
• rs104893854
• NM_002448.3:c.458C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002448.3(MSX1):​c.458C>T​(p.Pro153Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,451,518 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. P153Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MSX1 NM_002448.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18
• Publications: 7 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD gene.

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.458C>T	p.Pro153Leu	missense	Exon 1 of 2	NP_002439.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX1	ENST00000382723.5	TSL:1 MANE Select	c.458C>T	p.Pro153Leu	missense	Exon 1 of 2	ENSP00000372170.4
	ENSG00000308455	ENST00000834195.1		n.304-3568G>A		intron	N/A
	ENSG00000308455	ENST00000834196.1		n.49-3568G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000447 AC: 1 AN: 223710 AF XY: 0.00000802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1451518 Hom.: 0 Cov.: 38 AF XY: 0.0000125 AC XY: 9 AN XY: 722330

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5244

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111274

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.022	D
Vest4		0.42
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.49
gMVP		0.88
Mutation Taster		=28/72	disease causing

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: rs104893854; hg19: chr4-4862084;