rs538017286

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1BP6BS2

The NM_001412844.1(SULF1):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,610,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

SULF1
NM_001412844.1 start_lost

Scores

11
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
SULF1 (HGNC:20391): (sulfatase 1) This gene encodes an extracellular heparan sulfate endosulfatase. The encoded enzyme selectively removes 6-O-sulfate groups from heparan sulfate chains of heparan sulfate proteoglycans (HSPGs). The enzyme is secreted through the Golgi and is subsequently localized to the cell surface. The expression of this gene may be down-regulated in several types of cancer, including hepatocellular (HCC), ovarian and breast cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
Start lost variant, no new inframe start found.
BP6
Variant 8-69586473-G-A is Benign according to our data. Variant chr8-69586473-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221945.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SULF1NM_001128205.2 linkuse as main transcriptc.529G>A p.Gly177Ser missense_variant 7/23 ENST00000402687.9 NP_001121677.1 Q8IWU6A0A024R809

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SULF1ENST00000402687.9 linkuse as main transcriptc.529G>A p.Gly177Ser missense_variant 7/231 NM_001128205.2 ENSP00000385704.4 Q8IWU6

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152066
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000202
AC:
5
AN:
247934
Hom.:
0
AF XY:
0.0000298
AC XY:
4
AN XY:
134128
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000548
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000377
AC:
55
AN:
1458780
Hom.:
0
Cov.:
31
AF XY:
0.0000441
AC XY:
32
AN XY:
725676
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:
0.0000486
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152184
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000302
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 28, 2023This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 177 of the SULF1 protein (p.Gly177Ser). This variant is present in population databases (rs538017286, gnomAD 0.005%). This missense change has been observed in individual(s) with ocular developmental anomalies (PMID: 26893459). ClinVar contains an entry for this variant (Variation ID: 221945). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Anophthalmia-microphthalmia syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingPaul Sabatier University EA-4555, Paul Sabatier UniversityJan 01, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;D;D;D
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;.;.;.
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.86
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
M;M;M;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.5
D;D;D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0030
D;D;D;D
Sift4G
Uncertain
0.0070
D;D;D;D
Polyphen
0.63
P;P;P;P
Vest4
0.90
MutPred
0.52
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.83
MPC
0.99
ClinPred
0.56
D
GERP RS
5.9
Varity_R
0.81
gMVP
0.93

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

LitVar

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

Other links and lift over

dbSNP: rs538017286; hg19: chr8-70498708; API