rs4889839

Positions:

• chr17-80215164-G-A
• chr17-80215164-G-C
• chr17-80215164-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000199.5(SGSH):​c.250-26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,581,696 control chromosomes in the GnomAD database, including 212,596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22858 hom., cov: 33)
  • Exomes 𝑓: 0.51 (189738 hom.)
• Consequence: SGSH NM_000199.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.35

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 17-80215164-G-A is Benign according to our data. Variant chr17-80215164-G-A is described in ClinVar as [Benign]. Clinvar id is 255515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80215164-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSH	NM_000199.5	c.250-26C>T		intron_variant		ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.250-26C>T		intron_variant		1	NM_000199.5	ENSP00000314606	P1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82690 AN: 151962 Hom.: 22837 Cov.: 33

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.533

GnomAD3 exomes AF: 0.510 AC: 119007 AN: 233552 Hom.: 30573 AF XY: 0.513 AC XY: 65535 AN XY: 127680

Gnomad AFR exome AF: 0.650

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.487

Gnomad EAS exome AF: 0.600

Gnomad SAS exome AF: 0.519

Gnomad FIN exome AF: 0.501

Gnomad NFE exome AF: 0.512

Gnomad OTH exome AF: 0.520

GnomAD4 exome AF: 0.513 AC: 733659 AN: 1429616 Hom.: 189738 Cov.: 27 AF XY: 0.513 AC XY: 365816 AN XY: 712466

Gnomad4 AFR exome AF: 0.661

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.484

Gnomad4 EAS exome AF: 0.675

Gnomad4 SAS exome AF: 0.523

Gnomad4 FIN exome AF: 0.497

Gnomad4 NFE exome AF: 0.508

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.544 AC: 82751 AN: 152080 Hom.: 22858 Cov.: 33 AF XY: 0.543 AC XY: 40339 AN XY: 74354

Gnomad4 AFR AF: 0.647

Gnomad4 AMR AF: 0.446

Gnomad4 ASJ AF: 0.476

Gnomad4 EAS AF: 0.615

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.509

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.533

Alfa AF: 0.497 Hom.: 11553

Bravo AF: 0.544

Asia WGS AF: 0.567 AC: 1971 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Mucopolysaccharidosis, MPS-III-A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.046
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

Other links and lift over

dbSNP: rs4889839; hg19: chr17-78188963;