chr22-40361541-A-G

Variant names:

• chr22-40361541-A-G
• rs1006262492
• NM_000026.4:c.916A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000026.4(ADSL):​c.916A>G​(p.Ser306Gly) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADSL NM_000026.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000026.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

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.916A>G	p.Ser306Gly	missense	Exon 9 of 13	NP_000017.1	X5D8S6
	ADSL	NM_001410812.1		c.916A>G	p.Ser306Gly	missense	Exon 9 of 14	NP_001397741.1	A0A7P0Z472
	ADSL	NM_001363840.3		c.916A>G	p.Ser306Gly	missense	Exon 9 of 14	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.916A>G	p.Ser306Gly	missense	Exon 9 of 13	ENSP00000485525.1	P30566-1
	ADSL	ENST00000342312.9	TSL:1	c.916A>G	p.Ser306Gly	missense	Exon 9 of 12	ENSP00000341429.6	P30566-2
	ADSL	ENST00000480775.3	TSL:1	n.*279A>G		non_coding_transcript_exon	Exon 9 of 13	ENSP00000485462.2	A0A096LP92

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Benign	0.21
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.53
Sift	Benign	0.040	D
Sift4G	Benign	0.088	T
Polyphen		0.19	B
Vest4		0.56
MutPred		0.74		Loss of disorder (P = 0.0649)
MVP		0.76
MPC		0.33
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.83
gMVP		0.91
Mutation Taster		=47/53	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: rs1006262492; hg19: chr22-40757545;