Variant chr14-104729895-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_199165.2(ADSS1):c.3G>C(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 0.000000735 in 1,359,938 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: not found (cov: 29)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

ADSS1
NM_199165.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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:

ADSS1 (HGNC:):

ADSS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADSS1	NM_152328.5 linkuse as main transcript	c.193-5125G>C		intron_variant		ENST00000330877.7	NP_689541.1	Q8N142-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADSS1	ENST00000330877.7 linkuse as main transcript	c.193-5125G>C		intron_variant		1	NM_152328.5	ENSP00000331260.2		Q8N142-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000145

AC:

AN:

137748

Hom.:

AF XY:

0.0000273

AC XY:

AN XY:

73262

show subpopulations

Gnomad AFR exome

AF:

0.000257

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:

7.35e-7

AC:

AN:

1359938

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

666308

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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.:

ESP6500AA

AF:

0.00804

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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 (rs150558753, gnomAD 0.03%). 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: 1681873). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.89

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.015

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.040

REVEL

Benign

0.083

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

0.19

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)

0.12

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