dbSNP rs9894254: SGSH:p.Val361Ile (chr17-80210880-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000199.5(SGSH):c.1081G>A(p.Val361Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,612,936 control chromosomes in the GnomAD database, including 2,637 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V361V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.075 ( 621 hom., cov: 33)

Exomes 𝑓: 0.049 ( 2016 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 3.23

Publications

27 publications found

Variant links:

Genes affected

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

SGSH links:

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

CARD14 Gene-Disease associations (from GenCC):

familial pityriasis rubra pilaris
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
psoriasis 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

CARD14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000199.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0019078851).

BP6

Variant 17-80210880-C-T is Benign according to our data. Variant chr17-80210880-C-T is described in ClinVar as Benign. ClinVar VariationId is 92607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000199.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGSH	NM_000199.5	MANE Select	c.1081G>A	p.Val361Ile	missense	Exon 8 of 8	NP_000190.1	P51688
SGSH	NM_001352921.3		c.*168G>A		3_prime_UTR	Exon 8 of 8	NP_001339850.1
SGSH	NM_001352922.2		c.*131G>A		3_prime_UTR	Exon 9 of 9	NP_001339851.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGSH	ENST00000326317.11	TSL:1 MANE Select	c.1081G>A	p.Val361Ile	missense	Exon 8 of 8	ENSP00000314606.6	P51688
SGSH	ENST00000575282.5	TSL:1	n.3964G>A		non_coding_transcript_exon	Exon 5 of 5
SGSH	ENST00000874335.1		c.1117G>A	p.Val373Ile	missense	Exon 9 of 9	ENSP00000544394.1

Frequencies

GnomAD3 genomes

AF:

0.0754

AC:

11470

AN:

152152

Hom.:

620

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0441

Gnomad ASJ

AF:

0.0499

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0261

Gnomad FIN

AF:

0.0756

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0478

Gnomad OTH

AF:

0.0645

GnomAD2 exomes

AF:

0.0501

AC:

12507

AN:

249790

AF XY:

0.0488

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.0311

Gnomad ASJ exome

AF:

0.0471

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0729

Gnomad NFE exome

AF:

0.0507

Gnomad OTH exome

AF:

0.0530

GnomAD4 exome

AF:

0.0486

AC:

70977

AN:

1460668

Hom.:

2016

Cov.:

AF XY:

0.0477

AC XY:

34693

AN XY:

726580

show subpopulations

African (AFR)

AF:

0.153

AC:

5121

AN:

33478

American (AMR)

AF:

0.0328

AC:

1466

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0480

AC:

1255

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0328

AC:

2827

AN:

86254

European-Finnish (FIN)

AF:

0.0731

AC:

3822

AN:

52276

Middle Eastern (MID)

AF:

0.0765

AC:

441

AN:

5768

European-Non Finnish (NFE)

AF:

0.0475

AC:

52852

AN:

1111964

Other (OTH)

AF:

0.0528

AC:

3187

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

4470

8940

13409

17879

22349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2014

4028

6042

8056

10070

<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:

0.0754

AC:

11487

AN:

152268

Hom.:

621

Cov.:

AF XY:

0.0736

AC XY:

5483

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.151

AC:

6274

AN:

41546

American (AMR)

AF:

0.0440

AC:

673

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0499

AC:

173

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0263

AC:

127

AN:

4832

European-Finnish (FIN)

AF:

0.0756

AC:

801

AN:

10602

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0478

AC:

3254

AN:

68008

Other (OTH)

AF:

0.0639

AC:

135

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

549

1098

1648

2197

2746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0565

Hom.:

1108

Bravo

AF:

0.0771

TwinsUK

AF:

0.0499

AC:

185

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.143

AC:

629

ESP6500EA

AF:

0.0508

AC:

437

ExAC

AF:

0.0533

AC:

6473

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0463

EpiControl

AF:

0.0491

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis, MPS-III-A (6)

not specified (5)

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.050

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

3.2

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.66

REVEL

Benign

0.20

Sift

Benign

0.24

Sift4G

Benign

0.19

Polyphen

0.065

Vest4

0.11

MPC

0.20

ClinPred

0.0091

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.65

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over