Genetic Variant MSX1:c.*68C>T (chr4-4863211-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002448.3(MSX1):c.*68C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,491,052 control chromosomes in the GnomAD database, including 880 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.017 ( 134 hom., cov: 32)

Exomes 𝑓: 0.012 ( 746 hom. )

Consequence

MSX1
NM_002448.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.392

Publications

13 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX1	NM_002448.3 link	c.*68C>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000382723.5	NP_002439.2	P28360

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSX1	ENST00000382723.5 link	c.*68C>T	3_prime_UTR_variant	Exon 2 of 2	1	NM_002448.3	ENSP00000372170.4	P28360
ENSG00000308455	ENST00000834195.1 link	n.303+5597G>A	intron_variant	Intron 2 of 2
ENSG00000308455	ENST00000834196.1 link	n.48+4452G>A	intron_variant	Intron 1 of 1
MSX1	ENST00000468421.1 link	n.*183C>T	downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2581

AN:

152188

Hom.:

127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00388

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0785

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.129

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00473

Gnomad OTH

AF:

0.0249

GnomAD4 exome

AF:

0.0122

AC:

16304

AN:

1338746

Hom.:

746

Cov.:

AF XY:

0.0122

AC XY:

8113

AN XY:

663844

show subpopulations

African (AFR)

AF:

0.00316

AC:

AN:

31020

American (AMR)

AF:

0.124

AC:

4456

AN:

35904

Ashkenazi Jewish (ASJ)

AF:

0.00848

AC:

209

AN:

24646

East Asian (EAS)

AF:

0.126

AC:

4564

AN:

36336

South Asian (SAS)

AF:

0.0230

AC:

1804

AN:

78386

European-Finnish (FIN)

AF:

0.000381

AC:

AN:

34096

Middle Eastern (MID)

AF:

0.00668

AC:

AN:

4040

European-Non Finnish (NFE)

AF:

0.00392

AC:

4064

AN:

1037944

Other (OTH)

AF:

0.0190

AC:

1069

AN:

56374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

837

1674

2511

3348

4185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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

AF:

0.0170

AC:

2595

AN:

152306

Hom.:

134

Cov.:

AF XY:

0.0186

AC XY:

1384

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00387

AC:

161

AN:

41584

American (AMR)

AF:

0.0796

AC:

1218

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.129

AC:

663

AN:

5158

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4822

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00473

AC:

322

AN:

68030

Other (OTH)

AF:

0.0251

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

232

348

464

580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00990

Hom.:

Bravo

AF:

0.0236

Asia WGS

AF:

0.0870

AC:

302

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.8

(source)

DANN

Benign

0.89

PhyloP100

0.39

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over