rs7503034

Variant names:

• chr17-80210594-C-T
• rs7503034
• NM_000199.5:c.1367G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80210594-C-T
• chr17-80210594-C-G

Variant summary

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

The NM_000199.5(SGSH):​c.1367G>A​(p.Arg456His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,612,796 control chromosomes in the GnomAD database, including 93,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R456L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (7950 hom., cov: 31)
  • Exomes 𝑓: 0.34 (85775 hom.)
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.459
• Publications: 64 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=3.778287E-5).
• BP6: Variant 17-80210594-C-T is Benign according to our data. Variant chr17-80210594-C-T is described in ClinVar as Benign. ClinVar VariationId is 92610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.437 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	NM_000199.5	MANE Select	c.1367G>A	p.Arg456His	missense	Exon 8 of 8	NP_000190.1	P51688
	SGSH	NM_001352921.3		c.*454G>A		3_prime_UTR	Exon 8 of 8	NP_001339850.1
	SGSH	NM_001352922.2		c.*417G>A		3_prime_UTR	Exon 9 of 9	NP_001339851.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	ENST00000326317.11	TSL:1 MANE Select	c.1367G>A	p.Arg456His	missense	Exon 8 of 8	ENSP00000314606.6	P51688
	SGSH	ENST00000575282.5	TSL:1	n.4250G>A		non_coding_transcript_exon	Exon 5 of 5
	SGSH	ENST00000874335.1		c.1403G>A	p.Arg468His	missense	Exon 9 of 9	ENSP00000544394.1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47998 AN: 151848 Hom.: 7937 Cov.: 31

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.342

GnomAD2 exomes AF: 0.369 AC: 91556 AN: 248374 AF XY: 0.364

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.422

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.339 AC: 495325 AN: 1460830 Hom.: 85775 Cov.: 54 AF XY: 0.341 AC XY: 247653 AN XY: 726716

African (AFR) AF: 0.212 AC: 7086 AN: 33478

American (AMR) AF: 0.528 AC: 23571 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 9299 AN: 26116

East Asian (EAS) AF: 0.338 AC: 13390 AN: 39662

South Asian (SAS) AF: 0.394 AC: 33980 AN: 86226

European-Finnish (FIN) AF: 0.352 AC: 18582 AN: 52858

Middle Eastern (MID) AF: 0.336 AC: 1938 AN: 5766

European-Non Finnish (NFE) AF: 0.330 AC: 366799 AN: 1111754

Other (OTH) AF: 0.343 AC: 20680 AN: 60370

GnomAD4 genome AF: 0.316 AC: 48039 AN: 151966 Hom.: 7950 Cov.: 31 AF XY: 0.321 AC XY: 23802 AN XY: 74254

African (AFR) AF: 0.219 AC: 9097 AN: 41446

American (AMR) AF: 0.446 AC: 6816 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1231 AN: 3468

East Asian (EAS) AF: 0.401 AC: 2063 AN: 5150

South Asian (SAS) AF: 0.402 AC: 1931 AN: 4804

European-Finnish (FIN) AF: 0.340 AC: 3597 AN: 10566

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22305 AN: 67938

Other (OTH) AF: 0.342 AC: 720 AN: 2108

Alfa AF: 0.328 Hom.: 38131

Bravo AF: 0.321

TwinsUK AF: 0.331 AC: 1228

ALSPAC AF: 0.316 AC: 1216

ESP6500AA AF: 0.221 AC: 973

ESP6500EA AF: 0.331 AC: 2850

ExAC AF: 0.354 AC: 42908

Asia WGS AF: 0.378 AC: 1316 AN: 3478

EpiCase AF: 0.332

EpiControl AF: 0.335

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Mucopolysaccharidosis, MPS-III-A (5)
-	-	4	not provided (4)
-	-	4	not specified (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.89
DANN	Benign	0.92
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.000038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.46
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.17
Sift	Benign	0.19	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.24
ClinPred		0.0039	T
GERP RS		-6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.56
Mutation Taster		=71/29	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: rs7503034; hg19: chr17-78184393; COSMIC: COSV58338728; COSMIC: COSV58338728;