chr22-50627172-G-A

Variant names:

• chr22-50627172-G-A
• rs6151412
• NM_000487.6:c.459C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000487.6(ARSA):​c.459C>T​(p.His153His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0435 in 1,611,236 control chromosomes in the GnomAD database, including 1,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (310 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1628 hom.)
• Consequence: ARSA NM_000487.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.474
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 22-50627172-G-A is Benign according to our data. Variant chr22-50627172-G-A is described in ClinVar as Benign. ClinVar VariationId is 93123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.474 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0994 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.459C>T	p.His153His	synonymous	Exon 2 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.459C>T	p.His153His	synonymous	Exon 3 of 9	NP_001078894.2
	ARSA	NM_001085426.3		c.459C>T	p.His153His	synonymous	Exon 3 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.459C>T	p.His153His	synonymous	Exon 2 of 8	ENSP00000216124.5
	ARSA	ENST00000356098.9	TSL:1	c.459C>T	p.His153His	synonymous	Exon 3 of 9	ENSP00000348406.5
	ARSA	ENST00000395619.3	TSL:5	c.459C>T	p.His153His	synonymous	Exon 3 of 9	ENSP00000378981.3

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 8540 AN: 152182 Hom.: 309 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00997

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0554

GnomAD2 exomes AF: 0.0338 AC: 8139 AN: 240752 AF XY: 0.0329

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0354

GnomAD4 exome AF: 0.0422 AC: 61597 AN: 1458936 Hom.: 1628 Cov.: 33 AF XY: 0.0409 AC XY: 29689 AN XY: 725454

African (AFR) AF: 0.106 AC: 3536 AN: 33408

American (AMR) AF: 0.0289 AC: 1288 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 596 AN: 25976

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39632

South Asian (SAS) AF: 0.00657 AC: 566 AN: 86154

European-Finnish (FIN) AF: 0.0130 AC: 686 AN: 52738

Middle Eastern (MID) AF: 0.0222 AC: 128 AN: 5758

European-Non Finnish (NFE) AF: 0.0470 AC: 52224 AN: 1110420

Other (OTH) AF: 0.0427 AC: 2571 AN: 60228

GnomAD4 genome AF: 0.0561 AC: 8548 AN: 152300 Hom.: 310 Cov.: 33 AF XY: 0.0530 AC XY: 3946 AN XY: 74476

African (AFR) AF: 0.102 AC: 4237 AN: 41568

American (AMR) AF: 0.0465 AC: 712 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00434 AC: 21 AN: 4834

European-Finnish (FIN) AF: 0.00997 AC: 106 AN: 10628

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0462 AC: 3143 AN: 68000

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0527 Hom.: 229

Bravo AF: 0.0612

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0456

EpiControl AF: 0.0469

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.0
DANN	Benign	0.48
PhyloP100		-0.47
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)		0.050		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: rs6151412; hg19: chr22-51065600;