22-40346469-T-TCCCGC

Variant names:

• chr22-40346469-T-TCCCGC
• rs1237603952
• ENST00000623632.4:c.-80_-76dupCCCCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000623632.4(ADSL):​c.-80_-76dupCCCCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,431,728 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: ADSL ENST00000623632.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.110
• Publications: 0 publications found

Genes affected

ADSL (HGNC:291): (adenylosuccinate lyase) The protein encoded by this gene belongs to the lyase 1 family. It is an essential enzyme involved in purine metabolism, and catalyzes two non-sequential reactions in the de novo purine biosynthetic pathway: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR) and the conversion of adenylosuccinate (S-AMP) to adenosine monophosphate (AMP). Mutations in this gene are associated with adenylosuccinase deficiency (ADSLD), a disorder marked with psychomotor retardation, epilepsy or autistic features. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ADSL Gene-Disease associations (from GenCC):

• adenylosuccinate lyase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ENSG00000284431 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 22-40346469-T-TCCCGC is Benign according to our data. Variant chr22-40346469-T-TCCCGC is described in ClinVar as Benign. ClinVar VariationId is 1628739.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000933 (142/152240) while in subpopulation AFR AF = 0.00313 (130/41552). AF 95% confidence interval is 0.00269. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000623632.4. 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
	ADSL	NM_000026.4	MANE Select	c.-90_-89insCCCGC		upstream_gene	N/A	NP_000017.1	X5D8S6
	ADSL	NM_001410812.1		c.-90_-89insCCCGC		upstream_gene	N/A	NP_001397741.1	A0A7P0Z472
	ADSL	NM_001363840.3		c.-90_-89insCCCGC		upstream_gene	N/A	NP_001350769.1	A0A1B0GWJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSL	ENST00000623632.4	TSL:5	c.-80_-76dupCCCCG		5_prime_UTR	Exon 1 of 10	ENSP00000485288.2	A0A096LNY5
	ADSL	ENST00000623063.3	TSL:1 MANE Select	c.-90_-89insCCCGC		upstream_gene	N/A	ENSP00000485525.1	P30566-1
	ADSL	ENST00000342312.9	TSL:1	c.-90_-89insCCCGC		upstream_gene	N/A	ENSP00000341429.6	P30566-2

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000154 AC: 197 AN: 1279488 Hom.: 2 Cov.: 20 AF XY: 0.000194 AC XY: 122 AN XY: 630170

African (AFR) AF: 0.00281 AC: 83 AN: 29518

American (AMR) AF: 0.000285 AC: 10 AN: 35074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24334

East Asian (EAS) AF: 0.00 AC: 0 AN: 34858

South Asian (SAS) AF: 0.00115 AC: 88 AN: 76594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34306

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4118

European-Non Finnish (NFE) AF: 0.00000304 AC: 3 AN: 986906

Other (OTH) AF: 0.000223 AC: 12 AN: 53780

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74454

African (AFR) AF: 0.00313 AC: 130 AN: 41552

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67986

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000997

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Adenylosuccinate lyase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11

Splicing

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

Other links and lift over

dbSNP: rs1237603952; hg19: chr22-40742473;