chr17-80210137-G-A

Variant names:

• chr17-80210137-G-A
• rs2071148
• ENST00000575282.5:n.4707C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000575282.5(SGSH):​n.4707C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,255,602 control chromosomes in the GnomAD database, including 198,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18626 hom., cov: 34)
  • Exomes 𝑓: 0.57 (179947 hom.)
• Consequence: SGSH ENST00000575282.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.351
• Publications: 13 publications found

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]

CARD14 Gene-Disease associations (from GenCC):

• familial pityriasis rubra pilaris

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-80210137-G-A is Benign according to our data. Variant chr17-80210137-G-A is described in ClinVar as [Benign]. Clinvar id is 325821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGSH	NM_000199.5	c.*315C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.*315C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_000199.5	ENSP00000314606.6

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72591 AN: 152062 Hom.: 18633 Cov.: 34

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.480

GnomAD4 exome AF: 0.567 AC: 625947 AN: 1103420 Hom.: 179947 Cov.: 36 AF XY: 0.566 AC XY: 296565 AN XY: 524192

African (AFR) AF: 0.266 AC: 6641 AN: 24940

American (AMR) AF: 0.418 AC: 5147 AN: 12322

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 7202 AN: 13880

East Asian (EAS) AF: 0.626 AC: 13810 AN: 22058

South Asian (SAS) AF: 0.497 AC: 21644 AN: 43590

European-Finnish (FIN) AF: 0.554 AC: 9049 AN: 16320

Middle Eastern (MID) AF: 0.483 AC: 1379 AN: 2854

European-Non Finnish (NFE) AF: 0.582 AC: 537410 AN: 923826

Other (OTH) AF: 0.542 AC: 23665 AN: 43630

GnomAD4 genome AF: 0.477 AC: 72593 AN: 152182 Hom.: 18626 Cov.: 34 AF XY: 0.477 AC XY: 35511 AN XY: 74400

African (AFR) AF: 0.281 AC: 11651 AN: 41532

American (AMR) AF: 0.434 AC: 6643 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1794 AN: 3472

East Asian (EAS) AF: 0.571 AC: 2952 AN: 5166

South Asian (SAS) AF: 0.494 AC: 2379 AN: 4820

European-Finnish (FIN) AF: 0.548 AC: 5798 AN: 10588

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39624 AN: 67994

Other (OTH) AF: 0.479 AC: 1013 AN: 2116

Alfa AF: 0.524 Hom.: 8944

Bravo AF: 0.456

Asia WGS AF: 0.516 AC: 1794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.56
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071148; hg19: chr17-78183936;