Genetic Variant NM_006745.5:c.731A>C (chr4-165341795-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_006745.5(MSMO1):c.731A>C(p.Tyr244Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. Y244C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MSMO1
NM_006745.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.09

Publications

3 publications found

Variant links:

Genes affected

MSMO1 (HGNC:10545): (methylsterol monooxygenase 1) Sterol-C4-mehtyl oxidase-like protein was isolated based on its similarity to the yeast ERG25 protein. It contains a set of putative metal binding motifs with similarity to that seen in a family of membrane desaturases-hydroxylases. The protein is localized to the endoplasmic reticulum membrane and is believed to function in cholesterol biosynthesis. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MSMO1 Gene-Disease associations (from GenCC):

microcephaly-congenital cataract-psoriasiform dermatitis syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

MSMO1 links:

ENSG00000309940 (HGNC:):

ENSG00000309940 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-165341795-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 222975.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MSMO1	NM_006745.5 link	c.731A>C	p.Tyr244Ser	missense_variant	Exon 6 of 6	ENST00000261507.11	NP_006736.1
MSMO1	NM_001440534.1 link	c.731A>C	p.Tyr244Ser	missense_variant	Exon 6 of 6		NP_001427463.1
MSMO1	NM_001017369.3 link	c.338A>C	p.Tyr113Ser	missense_variant	Exon 5 of 5		NP_001017369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MSMO1	ENST00000261507.11 link	c.731A>C	p.Tyr244Ser	missense_variant	Exon 6 of 6	1	NM_006745.5	ENSP00000261507.6
MSMO1	ENST00000393766.6 link	c.338A>C	p.Tyr113Ser	missense_variant	Exon 5 of 5	2		ENSP00000377361.2
ENSG00000309940	ENST00000846052.1 link	n.342T>G		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461286

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111578

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.4

L;.

PhyloP100

9.1

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.87

MutPred

0.69

Gain of disorder (P = 0.0033);.;

MVP

0.81

MPC

1.2

ClinPred

0.99

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.90

gMVP

0.94

Mutation Taster

=11/89

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over