chr22-40361224-A-C

Variant names:

• chr22-40361224-A-C
• rs8135371
• NM_000026.4:c.793-49A>C

Variant summary

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

The NM_000026.4(ADSL):​c.793-49A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,559,676 control chromosomes in the GnomAD database, including 16,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1398 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14845 hom.)
• Consequence: ADSL NM_000026.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-40361224-A-C is Benign according to our data. Variant chr22-40361224-A-C is described in ClinVar as Benign. ClinVar VariationId is 670882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000026.4. 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.793-49A>C		intron	N/A	NP_000017.1	X5D8S6
	ADSL	NM_001410812.1		c.793-49A>C		intron	N/A	NP_001397741.1	A0A7P0Z472
	ADSL	NM_001363840.3		c.793-49A>C		intron	N/A	NP_001350769.1	A0A1B0GWJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSL	ENST00000623063.3	TSL:1 MANE Select	c.793-49A>C		intron	N/A	ENSP00000485525.1	P30566-1
	ADSL	ENST00000342312.9	TSL:1	c.793-49A>C		intron	N/A	ENSP00000341429.6	P30566-2
	ADSL	ENST00000480775.3	TSL:1	n.*107A>C		non_coding_transcript_exon	Exon 8 of 13	ENSP00000485462.2	A0A096LP92

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19742 AN: 151924 Hom.: 1390 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.0776

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.134 AC: 33625 AN: 251178 AF XY: 0.140

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0556

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0985

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.141 AC: 199149 AN: 1407634 Hom.: 14845 Cov.: 25 AF XY: 0.144 AC XY: 101038 AN XY: 703538

African (AFR) AF: 0.103 AC: 3319 AN: 32316

American (AMR) AF: 0.0585 AC: 2612 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2845 AN: 25778

East Asian (EAS) AF: 0.0905 AC: 3570 AN: 39438

South Asian (SAS) AF: 0.172 AC: 14643 AN: 85094

European-Finnish (FIN) AF: 0.211 AC: 11206 AN: 53172

Middle Eastern (MID) AF: 0.117 AC: 661 AN: 5660

European-Non Finnish (NFE) AF: 0.144 AC: 152756 AN: 1062956

Other (OTH) AF: 0.129 AC: 7537 AN: 58578

GnomAD4 genome AF: 0.130 AC: 19768 AN: 152042 Hom.: 1398 Cov.: 32 AF XY: 0.134 AC XY: 9966 AN XY: 74310

African (AFR) AF: 0.106 AC: 4382 AN: 41494

American (AMR) AF: 0.0775 AC: 1183 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3472

East Asian (EAS) AF: 0.0957 AC: 494 AN: 5160

South Asian (SAS) AF: 0.173 AC: 834 AN: 4818

European-Finnish (FIN) AF: 0.221 AC: 2327 AN: 10544

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9724 AN: 67970

Other (OTH) AF: 0.124 AC: 261 AN: 2108

Alfa AF: 0.133 Hom.: 3137

Bravo AF: 0.115

Asia WGS AF: 0.171 AC: 593 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.33
DANN	Benign	0.60
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8135371; hg19: chr22-40757228; COSMIC: COSV53407130; COSMIC: COSV53407130;