rs121913129

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_002448.3(MSX1):​c.605G>A​(p.Arg202His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

MSX1
NM_002448.3 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 9.82
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a DNA_binding_region Homeobox (size 59) in uniprot entity MSX1_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_002448.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-4862836-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14879.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953
PP5
Variant 4-4862836-G-A is Pathogenic according to our data. Variant chr4-4862836-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1299819.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-4862836-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MSX1NM_002448.3 linkuse as main transcriptc.605G>A p.Arg202His missense_variant 2/2 ENST00000382723.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSX1ENST00000382723.5 linkuse as main transcriptc.605G>A p.Arg202His missense_variant 2/21 NM_002448.3 P1
MSX1ENST00000468421.1 linkuse as main transcriptn.317G>A non_coding_transcript_exon_variant 2/23

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-4.8
D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0020
D
Vest4
0.97
MVP
0.97
MPC
1.9
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.95
gMVP
0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-4864563; API