rs743616

Variant names:

• chr22-50625611-G-C
• rs743616
• NM_000487.6:c.1178C>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):​c.1178C>G​(p.Thr393Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,612,938 control chromosomes in the GnomAD database, including 220,625 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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. T393A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.48 (17902 hom., cov: 32)
  • Exomes 𝑓: 0.52 (202723 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 0.122
• Publications: 61 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 -15 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000487.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50625611-GT-CC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1308665.
• 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=1.3175593E-5).
• BP6: Variant 22-50625611-G-C is Benign according to our data. Variant chr22-50625611-G-C is described in ClinVar as Benign. ClinVar VariationId is 21184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 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.1178C>G	p.Thr393Ser	missense	Exon 7 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.1178C>G	p.Thr393Ser	missense	Exon 8 of 9	NP_001078894.2
	ARSA	NM_001085426.3		c.1178C>G	p.Thr393Ser	missense	Exon 8 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.1178C>G	p.Thr393Ser	missense	Exon 7 of 8	ENSP00000216124.5
	ARSA	ENST00000356098.9	TSL:1	c.1178C>G	p.Thr393Ser	missense	Exon 8 of 9	ENSP00000348406.5
	ARSA	ENST00000395619.3	TSL:5	c.1178C>G	p.Thr393Ser	missense	Exon 8 of 9	ENSP00000378981.3

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72763 AN: 151796 Hom.: 17887 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.456

GnomAD2 exomes AF: 0.480 AC: 120494 AN: 251106 AF XY: 0.483

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.418

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.498

GnomAD4 exome AF: 0.523 AC: 763470 AN: 1461024 Hom.: 202723 Cov.: 74 AF XY: 0.521 AC XY: 378298 AN XY: 726796

African (AFR) AF: 0.382 AC: 12798 AN: 33476

American (AMR) AF: 0.420 AC: 18779 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 10896 AN: 26124

East Asian (EAS) AF: 0.343 AC: 13632 AN: 39696

South Asian (SAS) AF: 0.428 AC: 36883 AN: 86252

European-Finnish (FIN) AF: 0.595 AC: 31508 AN: 52992

Middle Eastern (MID) AF: 0.388 AC: 2237 AN: 5768

European-Non Finnish (NFE) AF: 0.546 AC: 606998 AN: 1111628

Other (OTH) AF: 0.493 AC: 29739 AN: 60370

GnomAD4 genome AF: 0.479 AC: 72803 AN: 151914 Hom.: 17902 Cov.: 32 AF XY: 0.481 AC XY: 35740 AN XY: 74256

African (AFR) AF: 0.390 AC: 16141 AN: 41408

American (AMR) AF: 0.454 AC: 6947 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3470

East Asian (EAS) AF: 0.310 AC: 1597 AN: 5150

South Asian (SAS) AF: 0.421 AC: 2031 AN: 4824

European-Finnish (FIN) AF: 0.597 AC: 6305 AN: 10566

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36636 AN: 67900

Other (OTH) AF: 0.453 AC: 955 AN: 2106

Alfa AF: 0.511 Hom.: 6579

Bravo AF: 0.463

TwinsUK AF: 0.540 AC: 2004

ALSPAC AF: 0.544 AC: 2095

ESP6500AA AF: 0.394 AC: 1736

ESP6500EA AF: 0.530 AC: 4560

ExAC AF: 0.483 AC: 58673

Asia WGS AF: 0.384 AC: 1337 AN: 3478

EpiCase AF: 0.520

EpiControl AF: 0.515

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Metachromatic leukodystrophy (7)
-	-	6	not specified (6)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.66
DANN	Benign	0.83
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.0024	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.12
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.29
Sift	Benign	0.47	T
Sift4G	Benign	0.41	T
Vest4		0.031
ClinPred		0.0040	T
GERP RS		-0.029
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.45
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs743616; hg19: chr22-51064039; COSMIC: COSV53350010; COSMIC: COSV53350010;