22-40365043-G-C

Variant names:

• chr22-40365043-G-C
• rs775671027
• NM_000026.4:c.1355G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_001410812.1(ADSL):​c.1355G>C​(p.Arg452Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R452L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADSL NM_001410812.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.81
• 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000284431 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001410812.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-40365042-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2086298.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 22-40365043-G-C is Pathogenic according to our data. Variant chr22-40365043-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1502354.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410812.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSL	NM_000026.4	MANE Select	c.1355G>C	p.Arg452Pro	missense	Exon 12 of 13	NP_000017.1
	ADSL	NM_001410812.1		c.1355G>C	p.Arg452Pro	missense	Exon 12 of 14	NP_001397741.1
	ADSL	NM_001363840.3		c.1355G>C	p.Arg452Pro	missense	Exon 12 of 14	NP_001350769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSL	ENST00000623063.3	TSL:1 MANE Select	c.1355G>C	p.Arg452Pro	missense	Exon 12 of 13	ENSP00000485525.1
	ADSL	ENST00000342312.9	TSL:1	c.1191+678G>C		intron	N/A	ENSP00000341429.6
	ADSL	ENST00000480775.3	TSL:1	n.*749G>C		non_coding_transcript_exon	Exon 12 of 13	ENSP00000485462.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.8
PrimateAI	Benign	0.47	T
REVEL	Pathogenic	0.94
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.68		Gain of glycosylation at R466 (P = 0.0515)
MVP		0.92
MPC		0.79
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.034	Neutral
Varity_R		1.0
gMVP		0.90
Mutation Taster		=1/99	disease causing

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: rs775671027; hg19: chr22-40761047;