22-50625228-C-T

Variant names:

• chr22-50625228-C-T
• rs148352371
• NM_000487.6:c.1447G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000487.6(ARSA):​c.1447G>A​(p.Glu483Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,609,656 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (3 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.137
• Publications: 3 publications found

Genes affected

ARSA (HGNC:713): (arylsulfatase A) The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]

ARSA Gene-Disease associations (from GenCC):

• metachromatic leukodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• metachromatic leukodystrophy, juvenile form

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000487.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 159 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.38013 (below the threshold of 3.09). Trascript score misZ: -0.56919 (below the threshold of 3.09). GenCC associations: The gene is linked to metachromatic leukodystrophy, juvenile form, metachromatic leukodystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0069256127).
• BP6: Variant 22-50625228-C-T is Benign according to our data. Variant chr22-50625228-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198734.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0023 (351/152324) while in subpopulation AFR AF = 0.00678 (282/41576). AF 95% confidence interval is 0.00613. There are 1 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000487.6. 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
	ARSA	NM_000487.6	MANE Select	c.1447G>A	p.Glu483Lys	missense	Exon 8 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.1447G>A	p.Glu483Lys	missense	Exon 9 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.1447G>A	p.Glu483Lys	missense	Exon 9 of 9	NP_001078895.2	A0A0C4DFZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	ENST00000216124.10	TSL:1 MANE Select	c.1447G>A	p.Glu483Lys	missense	Exon 8 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.1447G>A	p.Glu483Lys	missense	Exon 9 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.1447G>A	p.Glu483Lys	missense	Exon 9 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.000863 AC: 211 AN: 244416 AF XY: 0.000705

Gnomad AFR exome AF: 0.00691

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00133

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000421

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000556 AC: 810 AN: 1457332 Hom.: 3 Cov.: 32 AF XY: 0.000515 AC XY: 373 AN XY: 724614

African (AFR) AF: 0.00700 AC: 234 AN: 33414

American (AMR) AF: 0.00119 AC: 53 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.000847 AC: 22 AN: 25976

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85984

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 51978

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5754

European-Non Finnish (NFE) AF: 0.000342 AC: 380 AN: 1109982

Other (OTH) AF: 0.00150 AC: 90 AN: 60154

GnomAD4 genome AF: 0.00230 AC: 351 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74480

African (AFR) AF: 0.00678 AC: 282 AN: 41576

American (AMR) AF: 0.00203 AC: 31 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68030

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.000879 Hom.: 0

Bravo AF: 0.00287

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00614 AC: 27

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000850 AC: 103

EpiCase AF: 0.000600

EpiControl AF: 0.000594

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Metachromatic leukodystrophy (4)
-	-	1	ARSA-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.3
DANN	Benign	0.46
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.73	T
PhyloP100		-0.14
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.21
Sift	Benign	0.81	T
Sift4G	Benign	1.0	T
Vest4		0.12
MVP		0.50
ClinPred		0.00022	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.40
Mutation Taster		=84/16	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: rs148352371; hg19: chr22-51063656; COSMIC: COSV99332518; COSMIC: COSV99332518;