Genetic Variant ENST00000332972.9:c.3G>T (chr14-104729895-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The ENST00000332972.9(ADSS1):c.3G>T(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 0.00000147 in 1,359,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

ADSS1
ENST00000332972.9 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94

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 Uncertain_significance. Variant got 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 249 codons. Genomic position: 104740870. Lost 0.496 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADSS1	NM_152328.5 link	c.193-5125G>T		intron_variant	Intron 1 of 12	ENST00000330877.7	NP_689541.1	Q8N142-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADSS1	ENST00000330877.7 link	c.193-5125G>T		intron_variant	Intron 1 of 12	1	NM_152328.5	ENSP00000331260.2		Q8N142-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1359940

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

666310

show subpopulations

Gnomad4 AFR exome

AF:

0.0000694

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 1681874). This variant has not been reported in the literature in individuals affected with ADSSL1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ADSSL1 mRNA. The next in-frame methionine is located at codon 249. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.88

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.040

REVEL

Benign

0.080

Sift

Benign

0.055

Sift4G

Benign

0.29

Polyphen

0.0030

Vest4

0.19

MutPred

0.91

Gain of catalytic residue at S5 (P = 0);

MVP

0.14

ClinPred

0.39

GERP RS

0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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