11-121303539-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006918.5(SC5D):​c.164A>G​(p.Tyr55Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,804 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 1 hom. )

Consequence

SC5D
NM_006918.5 missense

Scores

5
9
5

Clinical Significance

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

Conservation

PhyloP100: 3.04

Publications

1 publications found
Variant links:
Genes affected
SC5D (HGNC:10547): (sterol-C5-desaturase) This gene encodes an enzyme of cholesterol biosynthesis. The encoded protein catalyzes the conversion of lathosterol into 7-dehydrocholesterol. Mutations in this gene have been associated with lathosterolosis. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]
SC5D Gene-Disease associations (from GenCC):
  • lathosterolosis
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13411224).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SC5DNM_006918.5 linkc.164A>G p.Tyr55Cys missense_variant Exon 2 of 5 ENST00000264027.9 NP_008849.2 O75845A0A024R3G4
SC5DNM_001024956.3 linkc.164A>G p.Tyr55Cys missense_variant Exon 2 of 5 NP_001020127.1 O75845A0A024R3G4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SC5DENST00000264027.9 linkc.164A>G p.Tyr55Cys missense_variant Exon 2 of 5 1 NM_006918.5 ENSP00000264027.4 O75845

Frequencies

GnomAD3 genomes
AF:
0.0000658
AC:
10
AN:
152066
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000103
AC:
26
AN:
251272
AF XY:
0.000103
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00149
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000527
AC:
77
AN:
1461738
Hom.:
1
Cov.:
31
AF XY:
0.0000591
AC XY:
43
AN XY:
727178
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00119
AC:
31
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000351
AC:
39
AN:
1111904
Other (OTH)
AF:
0.0000828
AC:
5
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<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:
0.0000658
AC:
10
AN:
152066
Hom.:
0
Cov.:
32
AF XY:
0.0000808
AC XY:
6
AN XY:
74288
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41406
American (AMR)
AF:
0.00
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00173
AC:
6
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10590
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
67996
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.545
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000270
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jul 29, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jun 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 55 of the SC5D protein (p.Tyr55Cys). This variant is present in population databases (rs778919181, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SC5D-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 C35"). 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
Benign
0.074
BayesDel_addAF
Uncertain
0.077
D
BayesDel_noAF
Uncertain
0.080
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D;D;D;D
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
.;D;D;D
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Uncertain
0.25
D
MutationAssessor
Pathogenic
3.0
M;.;.;M
PhyloP100
3.0
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-4.6
D;D;D;D
REVEL
Uncertain
0.49
Sift
Benign
0.050
D;D;D;D
Sift4G
Uncertain
0.026
D;T;D;D
Polyphen
0.068
B;B;B;B
Vest4
0.77
MutPred
0.47
Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP
0.88
MPC
0.18
ClinPred
0.33
T
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.32
gMVP
0.83
Mutation Taster
=55/45
polymorphism

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

Other links and lift over

dbSNP: rs778919181; hg19: chr11-121174248; COSMIC: COSV107246589; API