8-69575978-C-A

Position:

chr8-69575978-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000402687.9(SULF1):c.181C>A(p.Gln61Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

SULF1
ENST00000402687.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.88

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]

SULF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SULF1	NM_001128205.2 linkuse as main transcript	c.181C>A	p.Gln61Lys	missense_variant	6/23	ENST00000402687.9	NP_001121677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SULF1	ENST00000402687.9 linkuse as main transcript	c.181C>A	p.Gln61Lys	missense_variant	6/23	1	NM_001128205.2	ENSP00000385704	P1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

250214

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.000274

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000225

AC:

329

AN:

1461428

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

162

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000286

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000145

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000256

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000179

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.181C>A (p.Q61K) alteration is located in exon 6 (coding exon 2) of the SULF1 gene. This alteration results from a C to A substitution at nucleotide position 181, causing the glutamine (Q) at amino acid position 61 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 61 of the SULF1 protein (p.Gln61Lys). This variant is present in population databases (rs199820581, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SULF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1358569). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;D;.;D;D;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;.;D;.;.;D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.54

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.5

L;L;.;L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.2

N;N;N;N;N;D;N

REVEL

Pathogenic

0.67

Sift

Uncertain

0.024

D;D;T;D;D;D;T

Sift4G

Benign

0.16

T;T;D;T;T;D;T

Polyphen

0.13

B;B;.;B;B;.;.

Vest4

0.74

MVP

0.69

MPC

0.86

ClinPred

0.21

GERP RS

5.2

Varity_R

0.49

gMVP

0.90

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.

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