22-40346574-G-C

Position:

chr22-40346574-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000026.4(ADSL):c.16G>C(p.Asp6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,605,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ADSL
NM_000026.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.61

Variant links:

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 links:

ENSG00000284431 (HGNC:):

ENSG00000284431 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09253228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADSL	NM_000026.4 linkuse as main transcript	c.16G>C	p.Asp6His	missense_variant	1/13	ENST00000623063.3	NP_000017.1	P30566-1X5D8S6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADSL	ENST00000623063.3 linkuse as main transcript	c.16G>C	p.Asp6His	missense_variant	1/13	1	NM_000026.4	ENSP00000485525.1		P30566-1
ENSG00000284431	ENST00000639722.1 linkuse as main transcript	n.16G>C		non_coding_transcript_exon_variant	1/31	5		ENSP00000492828.1		A0A1W2PRX2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000388

AC:

AN:

232200

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

126464

show subpopulations

Gnomad AFR exome

AF:

0.0000702

Gnomad AMR exome

AF:

0.000242

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1452924

Hom.:

Cov.:

AF XY:

0.00000969

AC XY:

AN XY:

722250

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000183

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000667

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.16G>C (p.D6H) alteration is located in exon 1 (coding exon 1) of the ADSL gene. This alteration results from a G to C substitution at nucleotide position 16, causing the aspartic acid (D) at amino acid position 6 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 08, 2015

- -

Adenylosuccinate lyase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 6 of the ADSL protein (p.Asp6His). This variant is present in population databases (rs140064577, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ADSL-related conditions. ClinVar contains an entry for this variant (Variation ID: 281756). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADSL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.011

T;T;.;T;T;T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.093

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

0.55

.;N;N;.;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.54

.;.;N;.;N;.;.

REVEL

Benign

0.18

Sift

Uncertain

0.012

.;.;D;.;D;.;.

Sift4G

Uncertain

0.010

D;D;D;.;D;.;.

Polyphen

0.0

.;B;B;.;.;.;.

Vest4

0.14, 0.18, 0.21

MVP

0.94

MPC

0.36

ClinPred

0.075

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.26

gMVP

0.87

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over