Genetic Variant MSX1:p.Pro153Leu (chr4-4860357-C-T) – ACMG Classification: Likely_benign (-4 pts)

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.18

Publications

7 publications found

Variant links:

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)

MSX1 links:

ENSG00000308455 (HGNC:):

ENSG00000308455 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3 link	c.458C>T	p.Pro153Leu	missense_variant	Exon 1 of 2	ENST00000382723.5	NP_002439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MSX1	ENST00000382723.5 link	c.458C>T	p.Pro153Leu	missense_variant	Exon 1 of 2	1	NM_002448.3	ENSP00000372170.4
ENSG00000308455	ENST00000834195.1 link	n.304-3568G>A		intron_variant	Intron 2 of 2
ENSG00000308455	ENST00000834196.1 link	n.49-3568G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000447

AC:

AN:

223710

AF XY:

0.00000802

show subpopulations

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:

AN:

1451518

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

722330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5244

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111274

Other (OTH)

AF:

0.00

AC:

AN:

60112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.74

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.8

PhyloP100

7.2

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.70

Sift

Uncertain

0.017

Sift4G

Uncertain

0.022

Vest4

0.42

MVP

0.98

MPC

1.1

ClinPred

0.99

GERP RS

4.9

Varity_R

0.49

gMVP

0.88

Mutation Taster

=28/72

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over