chr4-165337885-T-C

Position:

• chr4-165337885-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000261507.11(MSMO1):​c.352T>C​(p.Tyr118His) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,460,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MSMO1 ENST00000261507.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19946161).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSMO1	NM_006745.5	c.352T>C	p.Tyr118His	missense_variant	3/6	ENST00000261507.11	NP_006736.1
MSMO1	XM_005263176.3	c.352T>C	p.Tyr118His	missense_variant	3/6		XP_005263233.1
MSMO1	NM_001017369.3	c.-42T>C		5_prime_UTR_variant	2/5		NP_001017369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSMO1	ENST00000261507.11	c.352T>C	p.Tyr118His	missense_variant	3/6	1	NM_006745.5	ENSP00000261507	P1
MSMO1	ENST00000504317.1	c.352T>C	p.Tyr118His	missense_variant	3/5	1		ENSP00000423633
MSMO1	ENST00000507013.5	c.352T>C	p.Tyr118His	missense_variant	3/5	2		ENSP00000425241
MSMO1	ENST00000393766.6	c.-42T>C		5_prime_UTR_variant	2/5	2		ENSP00000377361

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251028 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135680

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460982 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726868

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with MSMO1-related conditions. This variant is present in population databases (rs755943539, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 118 of the MSMO1 protein (p.Tyr118His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.070
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.56
MutPred		0.68		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP		0.23
MPC		0.39
ClinPred		0.31	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs755943539; hg19: chr4-166259037;