rs6151425

Variant names:

• chr22-50625640-G-A
• rs6151425
• NM_000487.6:c.1149C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-50625640-G-A
• chr22-50625640-G-C
• chr22-50625640-G-T

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.1149C>T​(p.Asp383Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,613,342 control chromosomes in the GnomAD database, including 1,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (136 hom., cov: 34)
  • Exomes 𝑓: 0.038 (1218 hom.)
• Consequence: ARSA NM_000487.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.31
• Publications: 12 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=-0.76).
• BP6: Variant 22-50625640-G-A is Benign according to our data. Variant chr22-50625640-G-A is described in ClinVar as Benign. ClinVar VariationId is 93117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0405 (6166/152270) while in subpopulation AFR AF = 0.0517 (2148/41560). AF 95% confidence interval is 0.0499. There are 136 homozygotes in GnomAd4. There are 3028 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 136 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.1149C>T	p.Asp383Asp	synonymous	Exon 7 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.1149C>T	p.Asp383Asp	synonymous	Exon 8 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.1149C>T	p.Asp383Asp	synonymous	Exon 8 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.1149C>T	p.Asp383Asp	synonymous	Exon 7 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.1149C>T	p.Asp383Asp	synonymous	Exon 8 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000861942.1		c.1144C>T	p.Arg382*	stop_gained	Exon 7 of 8	ENSP00000532001.1

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6166 AN: 152152 Hom.: 135 Cov.: 34

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0339 AC: 8506 AN: 251008 AF XY: 0.0346

Gnomad AFR exome AF: 0.0480

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0674

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0495

Gnomad NFE exome AF: 0.0373

Gnomad OTH exome AF: 0.0317

GnomAD4 exome AF: 0.0381 AC: 55736 AN: 1461072 Hom.: 1218 Cov.: 45 AF XY: 0.0380 AC XY: 27613 AN XY: 726862

African (AFR) AF: 0.0506 AC: 1693 AN: 33464

American (AMR) AF: 0.0177 AC: 793 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0670 AC: 1751 AN: 26120

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39698

South Asian (SAS) AF: 0.0332 AC: 2864 AN: 86246

European-Finnish (FIN) AF: 0.0462 AC: 2451 AN: 53082

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5768

European-Non Finnish (NFE) AF: 0.0393 AC: 43720 AN: 1111612

Other (OTH) AF: 0.0379 AC: 2287 AN: 60360

GnomAD4 genome AF: 0.0405 AC: 6166 AN: 152270 Hom.: 136 Cov.: 34 AF XY: 0.0407 AC XY: 3028 AN XY: 74472

African (AFR) AF: 0.0517 AC: 2148 AN: 41560

American (AMR) AF: 0.0297 AC: 455 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0271 AC: 131 AN: 4826

European-Finnish (FIN) AF: 0.0503 AC: 534 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0385 AC: 2619 AN: 67992

Other (OTH) AF: 0.0365 AC: 77 AN: 2112

Alfa AF: 0.0364 Hom.: 387

Bravo AF: 0.0396

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0385

EpiControl AF: 0.0353

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.64
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs6151425; hg19: chr22-51064068;