Variant chr14-104729893-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The ENST00000332972.9(ADSS1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 789,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 23)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADSS1
ENST00000332972.9 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.20

Variant links:

Genes affected

ADSS1 (HGNC:20093): (adenylosuccinate synthase 1) This gene encodes a member of the adenylosuccinate synthase family of proteins. The encoded muscle-specific enzyme plays a role in the purine nucleotide cycle by catalyzing the first step in the conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP). Mutations in this gene may cause adolescent onset distal myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ADSS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADSS1	NM_152328.5 linkuse as main transcript	c.193-5127A>G		intron_variant		ENST00000330877.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADSS1	ENST00000330877.7 linkuse as main transcript	c.193-5127A>G		intron_variant		1	NM_152328.5	P1	Q8N142-1

Frequencies

GnomAD3 genomes

AF:

0.000172

AC:

AN:

104886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000479

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000453

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000102

Gnomad OTH

AF:

0.000696

GnomAD3 exomes

AF:

0.0000271

AC:

AN:

73894

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

38730

show subpopulations

Gnomad AFR exome

AF:

0.000357

Gnomad AMR exome

AF:

0.00

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:

0.00000760

AC:

AN:

789150

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

391216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000973

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000595

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000210

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000169

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000181

AC:

AN:

104924

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

50436

show subpopulations

Gnomad4 AFR

AF:

0.000143

Gnomad4 AMR

AF:

0.000479

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000336

Gnomad4 FIN

AF:

0.000453

Gnomad4 NFE

AF:

0.000102

Gnomad4 OTH

AF:

0.000688

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change affects the initiator methionine of the ADSSL1 mRNA. The next in-frame methionine is located at codon 249. This variant is present in population databases (rs80097179, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ADSSL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1681872). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.8

DANN

Benign

0.089

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0013

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.023

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;N

PROVEAN

Benign

0.060

REVEL

Benign

0.096

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.11

MVP

0.061

ClinPred

0.024

GERP RS

-0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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