rs144285237

Variant names:

• chr17-80208249-C-G
• rs144285237
• NM_001366385.1:c.2919C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-80208249-C-G
• chr17-80208249-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001366385.1(CARD14):​c.2919C>G​(p.Asp973Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,581,668 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D973G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.875
• Publications: 5 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Myriad Women’s Health, PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033692718).
• BP6: Variant 17-80208249-C-G is Benign according to our data. Variant chr17-80208249-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00152 (231/152362) while in subpopulation AMR AF = 0.0049 (75/15308). AF 95% confidence interval is 0.00401. There are 3 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 231 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366385.1. 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
	CARD14	NM_001366385.1	MANE Select	c.2919C>G	p.Asp973Glu	missense	Exon 24 of 24	NP_001353314.1	Q9BXL6-1
	CARD14	NM_024110.4		c.2919C>G	p.Asp973Glu	missense	Exon 21 of 21	NP_077015.2	Q9BXL6-1
	CARD14	NR_047566.2		n.3056C>G		non_coding_transcript_exon	Exon 22 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	ENST00000648509.2	MANE Select	c.2919C>G	p.Asp973Glu	missense	Exon 24 of 24	ENSP00000498071.1	Q9BXL6-1
	CARD14	ENST00000344227.6	TSL:1	c.2919C>G	p.Asp973Glu	missense	Exon 21 of 21	ENSP00000344549.2	Q9BXL6-1
	CARD14	ENST00000651672.1		c.2946C>G	p.Asp982Glu	missense	Exon 23 of 23	ENSP00000499145.1	A0A494C1N2

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152244 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00173 AC: 342 AN: 197974 AF XY: 0.00179

Gnomad AFR exome AF: 0.000413

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00316

GnomAD4 exome AF: 0.00170 AC: 2423 AN: 1429306 Hom.: 3 Cov.: 33 AF XY: 0.00171 AC XY: 1212 AN XY: 707818

African (AFR) AF: 0.000210 AC: 7 AN: 33274

American (AMR) AF: 0.00170 AC: 66 AN: 38756

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 254 AN: 25388

East Asian (EAS) AF: 0.00 AC: 0 AN: 38636

South Asian (SAS) AF: 0.0000367 AC: 3 AN: 81636

European-Finnish (FIN) AF: 0.0000805 AC: 4 AN: 49686

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5698

European-Non Finnish (NFE) AF: 0.00180 AC: 1972 AN: 1096900

Other (OTH) AF: 0.00172 AC: 102 AN: 59332

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152362 Hom.: 3 Cov.: 33 AF XY: 0.00158 AC XY: 118 AN XY: 74518

African (AFR) AF: 0.000337 AC: 14 AN: 41596

American (AMR) AF: 0.00490 AC: 75 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00176 Hom.: 0

Bravo AF: 0.00171

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00210 AC: 18

ExAC AF: 0.00106 AC: 126

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	CARD14-related disorder (1)
-	-	1	Pityriasis rubra pilaris;C1864497:Psoriasis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.65
DANN	Benign	0.96
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.88
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.035
Sift	Benign	0.30	T
Sift4G	Benign	0.093	T
Polyphen		0.12	B
Vest4		0.045
MutPred		0.27		Gain of catalytic residue at D973 (P = 0.0998)
MVP		0.38
MPC		0.17
ClinPred		0.0052	T
GERP RS		-1.2
Varity_R		0.041
gMVP		0.24
Mutation Taster		=89/11	polymorphism

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: rs144285237; hg19: chr17-78182048;