chr22-50625049-T-C

Variant names:

• chr22-50625049-T-C
• rs6151429
• NM_000487.6:c.*96A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):​c.*96A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.073 in 1,343,902 control chromosomes in the GnomAD database, including 4,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (278 hom., cov: 32)
  • Exomes 𝑓: 0.075 (3812 hom.)
• Consequence: ARSA NM_000487.6 3_prime_UTR
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts P:1 U:2 B:13 O:4
• Conservation: PhyloP100: 0.972
• Publications: 80 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 22-50625049-T-C is Benign according to our data. Variant chr22-50625049-T-C is described in ClinVar as Benign|other. ClinVar VariationId is 3049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 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.*96A>G		3_prime_UTR	Exon 8 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.*96A>G		3_prime_UTR	Exon 9 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.*96A>G		3_prime_UTR	Exon 9 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.*96A>G		3_prime_UTR	Exon 8 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.*96A>G		3_prime_UTR	Exon 9 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.*96A>G		3_prime_UTR	Exon 9 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes AF: 0.0536 AC: 8153 AN: 152184 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0188

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0775

Gnomad OTH AF: 0.0592

GnomAD4 exome AF: 0.0755 AC: 89951 AN: 1191600 Hom.: 3812 Cov.: 19 AF XY: 0.0770 AC XY: 44704 AN XY: 580856

African (AFR) AF: 0.0121 AC: 318 AN: 26244

American (AMR) AF: 0.0479 AC: 971 AN: 20266

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 1948 AN: 18336

East Asian (EAS) AF: 0.0118 AC: 403 AN: 34288

South Asian (SAS) AF: 0.114 AC: 6928 AN: 60862

European-Finnish (FIN) AF: 0.0372 AC: 1122 AN: 30154

Middle Eastern (MID) AF: 0.132 AC: 457 AN: 3468

European-Non Finnish (NFE) AF: 0.0783 AC: 74180 AN: 947640

Other (OTH) AF: 0.0720 AC: 3624 AN: 50342

GnomAD4 genome AF: 0.0536 AC: 8170 AN: 152302 Hom.: 278 Cov.: 32 AF XY: 0.0522 AC XY: 3890 AN XY: 74478

African (AFR) AF: 0.0127 AC: 527 AN: 41566

American (AMR) AF: 0.0501 AC: 767 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3468

East Asian (EAS) AF: 0.0189 AC: 98 AN: 5190

South Asian (SAS) AF: 0.112 AC: 542 AN: 4828

European-Finnish (FIN) AF: 0.0365 AC: 388 AN: 10620

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0775 AC: 5274 AN: 68008

Other (OTH) AF: 0.0662 AC: 140 AN: 2116

Alfa AF: 0.0703 Hom.: 1462

Bravo AF: 0.0516

Asia WGS AF: 0.0930 AC: 322 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	4	Metachromatic leukodystrophy (9)
-	-	5	not specified (5)
-	-	4	not provided (5)
1	-	-	ARYLSULFATASE A PSEUDODEFICIENCY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.79
PhyloP100		0.97
Mutation Taster		=100/0	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: rs6151429; hg19: chr22-51063477;