22-50626894-A-G

Variant names:

• chr22-50626894-A-G
• rs113990230
• NM_000487.6:c.624T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000487.6(ARSA):​c.624T>C​(p.His208His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00907 in 1,613,476 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (142 hom.)
• Consequence: ARSA NM_000487.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.41
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 22-50626894-A-G is Benign according to our data. Variant chr22-50626894-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00944 (1438/152274) while in subpopulation NFE AF = 0.0146 (993/68014). AF 95% confidence interval is 0.0138. There are 10 homozygotes in GnomAd4. There are 760 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.624T>C	p.His208His	synonymous	Exon 3 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.624T>C	p.His208His	synonymous	Exon 4 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.624T>C	p.His208His	synonymous	Exon 4 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.624T>C	p.His208His	synonymous	Exon 3 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.624T>C	p.His208His	synonymous	Exon 4 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.624T>C	p.His208His	synonymous	Exon 4 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1438 AN: 152156 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00905 AC: 2268 AN: 250542 AF XY: 0.00893

Gnomad AFR exome AF: 0.000992

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00707

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0280

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00903 AC: 13195 AN: 1461202 Hom.: 142 Cov.: 33 AF XY: 0.00918 AC XY: 6670 AN XY: 726892

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00250 AC: 112 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00788 AC: 206 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.0288 AC: 1522 AN: 52832

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00978 AC: 10879 AN: 1111934

Other (OTH) AF: 0.00730 AC: 441 AN: 60382

GnomAD4 genome AF: 0.00944 AC: 1438 AN: 152274 Hom.: 10 Cov.: 33 AF XY: 0.0102 AC XY: 760 AN XY: 74462

African (AFR) AF: 0.00101 AC: 42 AN: 41550

American (AMR) AF: 0.00379 AC: 58 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0289 AC: 307 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0146 AC: 993 AN: 68014

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.0112 Hom.: 11

Bravo AF: 0.00672

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.00889

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.14
DANN	Benign	0.30
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113990230; hg19: chr22-51065322; COSMIC: COSV53350467; COSMIC: COSV53350467;