22-40354285-A-T

Variant names:

• chr22-40354285-A-T
• rs11089991
• NM_000026.4:c.440A>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000026.4(ADSL):​c.440A>T​(p.Lys147Met) variant causes a missense change. The variant allele was found at a frequency of 0.00245 in 1,614,214 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K147E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (37 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (42 hom.)
• Consequence: ADSL NM_000026.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.97
• Publications: 7 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 -18 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, 6 uncertain in NM_000026.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056613684).
• BP6: Variant 22-40354285-A-T is Benign according to our data. Variant chr22-40354285-A-T is described in ClinVar as Benign. ClinVar VariationId is 128278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1989/152342) while in subpopulation AFR AF = 0.0453 (1884/41558). AF 95% confidence interval is 0.0436. There are 37 homozygotes in GnomAd4. There are 952 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

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.440A>T	p.Lys147Met	missense	Exon 4 of 13	NP_000017.1	X5D8S6
	ADSL	NM_001410812.1		c.440A>T	p.Lys147Met	missense	Exon 4 of 14	NP_001397741.1	A0A7P0Z472
	ADSL	NM_001363840.3		c.440A>T	p.Lys147Met	missense	Exon 4 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.440A>T	p.Lys147Met	missense	Exon 4 of 13	ENSP00000485525.1	P30566-1
	ADSL	ENST00000342312.9	TSL:1	c.440A>T	p.Lys147Met	missense	Exon 4 of 12	ENSP00000341429.6	P30566-2
	ADSL	ENST00000480775.3	TSL:1	n.440A>T		non_coding_transcript_exon	Exon 4 of 13	ENSP00000485462.2	A0A096LP92

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1979 AN: 152224 Hom.: 37 Cov.: 31

Gnomad AFR AF: 0.0452

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00337 AC: 847 AN: 251494 AF XY: 0.00234

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00134 AC: 1964 AN: 1461872 Hom.: 42 Cov.: 30 AF XY: 0.00111 AC XY: 810 AN XY: 727238

African (AFR) AF: 0.0473 AC: 1582 AN: 33480

American (AMR) AF: 0.00235 AC: 105 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000764 AC: 85 AN: 1111998

Other (OTH) AF: 0.00300 AC: 181 AN: 60396

GnomAD4 genome AF: 0.0131 AC: 1989 AN: 152342 Hom.: 37 Cov.: 31 AF XY: 0.0128 AC XY: 952 AN XY: 74494

African (AFR) AF: 0.0453 AC: 1884 AN: 41558

American (AMR) AF: 0.00464 AC: 71 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68042

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00194 Hom.: 4

Bravo AF: 0.0151

ESP6500AA AF: 0.0456 AC: 201

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00409 AC: 496

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Adenylosuccinate lyase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.026
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0057	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.40	N
PhyloP100		5.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.42
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.0040	B
Vest4		0.47
MVP		0.96
MPC		0.41
ClinPred		0.029	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.80
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11089991; hg19: chr22-40750289;