rs6151415

Variant names:

• chr22-50626933-C-A
• rs6151415
• NM_000487.6:c.585G>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):​c.585G>T​(p.Trp195Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,613,172 control chromosomes in the GnomAD database, including 4,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (275 hom., cov: 33)
  • Exomes 𝑓: 0.070 (4138 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.05
• Publications: 27 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 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=0.004769802).
• BP6: Variant 22-50626933-C-A is Benign according to our data. Variant chr22-50626933-C-A is described in ClinVar as Benign. ClinVar VariationId is 93125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

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.585G>T	p.Trp195Cys	missense	Exon 3 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.585G>T	p.Trp195Cys	missense	Exon 4 of 9	NP_001078894.2
	ARSA	NM_001085426.3		c.585G>T	p.Trp195Cys	missense	Exon 4 of 9	NP_001078895.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	ENST00000216124.10	TSL:1 MANE Select	c.585G>T	p.Trp195Cys	missense	Exon 3 of 8	ENSP00000216124.5
	ARSA	ENST00000356098.9	TSL:1	c.585G>T	p.Trp195Cys	missense	Exon 4 of 9	ENSP00000348406.5
	ARSA	ENST00000395619.3	TSL:5	c.585G>T	p.Trp195Cys	missense	Exon 4 of 9	ENSP00000378981.3

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7779 AN: 152216 Hom.: 276 Cov.: 33

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0780

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0507

GnomAD2 exomes AF: 0.0529 AC: 13189 AN: 249174 AF XY: 0.0535

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.0750

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.0768

Gnomad OTH exome AF: 0.0586

GnomAD4 exome AF: 0.0703 AC: 102707 AN: 1460838 Hom.: 4138 Cov.: 34 AF XY: 0.0691 AC XY: 50188 AN XY: 726720

African (AFR) AF: 0.0110 AC: 367 AN: 33480

American (AMR) AF: 0.0281 AC: 1258 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 1805 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0224 AC: 1933 AN: 86256

European-Finnish (FIN) AF: 0.0718 AC: 3766 AN: 52476

Middle Eastern (MID) AF: 0.0517 AC: 298 AN: 5768

European-Non Finnish (NFE) AF: 0.0806 AC: 89645 AN: 1111936

Other (OTH) AF: 0.0601 AC: 3629 AN: 60370

GnomAD4 genome AF: 0.0511 AC: 7778 AN: 152334 Hom.: 275 Cov.: 33 AF XY: 0.0502 AC XY: 3738 AN XY: 74496

African (AFR) AF: 0.0150 AC: 623 AN: 41594

American (AMR) AF: 0.0339 AC: 519 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 281 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4826

European-Finnish (FIN) AF: 0.0780 AC: 828 AN: 10620

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5249 AN: 68018

Other (OTH) AF: 0.0502 AC: 106 AN: 2112

Alfa AF: 0.0676 Hom.: 1033

Bravo AF: 0.0458

TwinsUK AF: 0.0747 AC: 277

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.0771 AC: 663

ExAC AF: 0.0527 AC: 6402

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0796

EpiControl AF: 0.0787

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Metachromatic leukodystrophy (4)
-	-	3	not provided (3)
-	-	1	Citrullinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.0048
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.32	T
PhyloP100		1.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.42
Sift	Benign	0.036	D
Sift4G	Uncertain	0.032	D
Vest4		0.49
ClinPred		0.010	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.90
Mutation Taster		=71/29	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6151415; hg19: chr22-51065361; COSMIC: COSV53350176; COSMIC: COSV53350176;