5-78780659-C-T

Variant names:

• chr5-78780659-C-T
• rs1465993279
• NM_000046.5:c.1340G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000046.5(ARSB):​c.1340G>A​(p.Cys447Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.63

Genes affected

ARSB (HGNC:714): (arylsulfatase B) Arylsulfatase B encoded by this gene belongs to the sulfatase family. The arylsulfatase B homodimer hydrolyzes sulfate groups of N-Acetyl-D-galactosamine, chondriotin sulfate, and dermatan sulfate. The protein is targeted to the lysozyme. Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1340G>A	p.Cys447Tyr	missense_variant	Exon 8 of 8	ENST00000264914.10	NP_000037.2
ARSB	XM_011543390.2	c.1340G>A	p.Cys447Tyr	missense_variant	Exon 9 of 9		XP_011541692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.1340G>A	p.Cys447Tyr	missense_variant	Exon 8 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000521011.1	n.305G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.066
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.62
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.079	B
Vest4		0.78
MutPred		0.69		Loss of sheet (P = 0.0228);
MVP		0.88
MPC		0.62
ClinPred		0.85	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1465993279; hg19: chr5-78076482;