rs6151410

Variant names:

• chr22-50627388-G-A
• rs6151410
• NM_000487.6:c.243C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000487.6(ARSA):​c.243C>T​(p.Gly81Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,607,682 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (137 hom.)
• Consequence: ARSA NM_000487.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.607
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 22-50627388-G-A is Benign according to our data. Variant chr22-50627388-G-A is described in ClinVar as Benign. ClinVar VariationId is 281161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.607 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0755 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.243C>T	p.Gly81Gly	synonymous	Exon 2 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.243C>T	p.Gly81Gly	synonymous	Exon 3 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.243C>T	p.Gly81Gly	synonymous	Exon 3 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.243C>T	p.Gly81Gly	synonymous	Exon 2 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.243C>T	p.Gly81Gly	synonymous	Exon 3 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.243C>T	p.Gly81Gly	synonymous	Exon 3 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3419 AN: 152210 Hom.: 119 Cov.: 33

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00594 AC: 1376 AN: 231830 AF XY: 0.00453

Gnomad AFR exome AF: 0.0839

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000251

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.00250 AC: 3635 AN: 1455354 Hom.: 137 Cov.: 33 AF XY: 0.00210 AC XY: 1523 AN XY: 723856

African (AFR) AF: 0.0826 AC: 2762 AN: 33438

American (AMR) AF: 0.00480 AC: 213 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.00450 AC: 117 AN: 26024

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39586

South Asian (SAS) AF: 0.000163 AC: 14 AN: 85678

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49500

Middle Eastern (MID) AF: 0.00453 AC: 26 AN: 5738

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1110878

Other (OTH) AF: 0.00547 AC: 329 AN: 60164

GnomAD4 genome AF: 0.0225 AC: 3426 AN: 152328 Hom.: 120 Cov.: 33 AF XY: 0.0215 AC XY: 1601 AN XY: 74486

African (AFR) AF: 0.0778 AC: 3234 AN: 41584

American (AMR) AF: 0.00830 AC: 127 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68018

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.00765 Hom.: 22

Bravo AF: 0.0259

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Metachromatic leukodystrophy (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.9
DANN	Benign	0.77
PhyloP100		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=296/4	polymorphism (auto)

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: rs6151410; hg19: chr22-51065816; COSMIC: COSV53350781; COSMIC: COSV53350781;