4-165337848-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006745.5(MSMO1):c.315C>A(p.His105Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,230 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MSMO1
NM_006745.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.30

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSMO1	NM_006745.5 link	c.315C>A	p.His105Gln	missense_variant	Exon 3 of 6	ENST00000261507.11	NP_006736.1	Q15800-1
MSMO1	XM_005263176.3 link	c.315C>A	p.His105Gln	missense_variant	Exon 3 of 6		XP_005263233.1	Q15800-1
MSMO1	NM_001017369.3 link	c.-79C>A		5_prime_UTR_variant	Exon 2 of 5		NP_001017369.1	Q15800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSMO1	ENST00000261507.11 link	c.315C>A	p.His105Gln	missense_variant	Exon 3 of 6	1	NM_006745.5	ENSP00000261507.6	Q15800-1
MSMO1	ENST00000504317.1 link	c.315C>A	p.His105Gln	missense_variant	Exon 3 of 5	1		ENSP00000423633.1	D6R952
MSMO1	ENST00000507013.5 link	c.315C>A	p.His105Gln	missense_variant	Exon 3 of 5	2		ENSP00000425241.1	D6RDP9
MSMO1	ENST00000393766 link	c.-79C>A		5_prime_UTR_variant	Exon 2 of 5	2		ENSP00000377361.2	Q15800-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461074

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726902

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.315C>A (p.H105Q) alteration is located in exon 3 (coding exon 2) of the MSMO1 gene. This alteration results from a C to A substitution at nucleotide position 315, causing the histidine (H) at amino acid position 105 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Dec 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 105 of the MSMO1 protein (p.His105Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSMO1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.48

T;T;T

Eigen

Benign

-0.098

Eigen_PC

Benign

0.0012

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Benign

-0.96

MutationAssessor

Pathogenic

3.3

M;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.8

D;D;D

REVEL

Uncertain

0.34

Sift

Benign

0.088

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.91

P;.;B

Vest4

0.88

MutPred

0.65

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

0.52

MPC

0.51

ClinPred

0.94

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over