22-50623623-G-T

Variant names:

• chr22-50623623-G-T
• rs6009939
• NM_000487.6:c.*1522C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000487.6(ARSA):​c.*1522C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 151,934 control chromosomes in the GnomAD database, including 5,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.27 (5643 hom., cov: 31)
• Consequence: ARSA NM_000487.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.336
• 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-50623623-G-T is Benign according to our data. Variant chr22-50623623-G-T is described in ClinVar as Benign. ClinVar VariationId is 342198.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.386 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.*1522C>A		3_prime_UTR	Exon 8 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.*1522C>A		3_prime_UTR	Exon 9 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.*1522C>A		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.*1522C>A		3_prime_UTR	Exon 8 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000608497.1	TSL:3	n.*93+151C>A		intron	N/A	ENSP00000477013.1	V9GYR0

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40379 AN: 151816 Hom.: 5624 Cov.: 31

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.266 AC: 40449 AN: 151934 Hom.: 5643 Cov.: 31 AF XY: 0.267 AC XY: 19855 AN XY: 74252

African (AFR) AF: 0.320 AC: 13269 AN: 41426

American (AMR) AF: 0.319 AC: 4862 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 919 AN: 3472

East Asian (EAS) AF: 0.401 AC: 2059 AN: 5140

South Asian (SAS) AF: 0.317 AC: 1524 AN: 4814

European-Finnish (FIN) AF: 0.215 AC: 2276 AN: 10570

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14797 AN: 67932

Other (OTH) AF: 0.257 AC: 543 AN: 2110

Alfa AF: 0.133 Hom.: 246

Bravo AF: 0.278

Asia WGS AF: 0.367 AC: 1276 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Metachromatic leukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.44
PhyloP100		0.34

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6009939; hg19: chr22-51062051;