rs140614802

Positions:

chr14-104741231-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_152328.5(ADSS1):c.781G>A(p.Asp261Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,597,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ADSS1
NM_152328.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 9.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 14-104741231-G-A is Pathogenic according to our data. Variant chr14-104741231-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 243025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADSS1	NM_152328.5 linkuse as main transcript	c.781G>A	p.Asp261Asn	missense_variant	8/13	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.781G>A	p.Asp261Asn	missense_variant	8/13	1	NM_152328.5	ENSP00000331260.2		Q8N142-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000340

AC:

AN:

235044

Hom.:

AF XY:

0.0000392

AC XY:

AN XY:

127604

show subpopulations

Gnomad AFR exome

AF:

0.0000627

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000115

Gnomad SAS exome

AF:

0.000142

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.0000180

AC:

AN:

1444988

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

718014

show subpopulations

Gnomad4 AFR exome

AF:

0.0000306

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.000154

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000543

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Myopathy, distal, 5

Pathogenic:5Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 09, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Homozygous variant classified as Pathogenic and reported on 10-19-2017 by Lab or GTR ID 505801. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000243025, PMID:26506222). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 26506222) and co-segregated with Myopathy, distal, 5 in multiple affected family members (PMID: 26506222). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PS3_S). A missense variant is a common mechanism associated with Myopathy, distal, 5. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000340). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The homozygous p.Asp304Asn variant in ADSS1 was identified by our study in 1 individual with distal myopathy 5. The variant has been reported in 4 Korean individuals with distal myopathy 5 (PMID: 26506222), segregated with disease in 4 affected relatives from 2 families (PMID: 26506222), and has been identified in 0.01% (4/28258) of South Asian, 0.01% (2/17392) of East Asian, and 0.006% (1/15946) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs140614802). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 243025) as pathogenic by NIH Undiagnosed Diseases Network and OMIM, and as likely pathogenic by Fulgent Genetics. Animal models in zebrafish have shown that this variant causes distal myopathy 5 (PMID: 26506222). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 1 affected homozygote, in combination with a reported variant of uncertain significance that is confirmed in trans, and in 4 individuals with distal myopathy 5 increases the likelihood that the p.Asp304Asn variant is pathogenic (Variation ID: 243026, PMID: 26506222). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3, PP1 (Richards 2015). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces aspartic acid with asparagine at codon 304 of the ADSSL1 protein (p.Asp304Asn). This variant is present in population databases (rs140614802, gnomAD 0.01%). This missense change has been observed in individuals with distal myopathy (PMID: 26506222, 32331917). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 243025). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects ADSSL1 function (PMID: 26506222). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2020	Published functional studies demonstrate a damaging effect with reduced enzymatic activity compared to the wild type in vitro. In addition, D304N mRNAs injected into zebrafish embryos resulted in a defective skeletal muscle phenotype (Park et al., 2016); This variant is associated with the following publications: (PMID: 32646962, 32331917, 30853170, 28268051, 26506222) -

ADSS1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2023

The ADSS1 c.910G>A variant is predicted to result in the amino acid substitution p.Asp304Asn. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with myopathy (Mroczek et al. 2020. PubMed ID: 32331917; Park et al. 2016. PubMed ID: 26506222). Functional studies showed the the variant led to decreased enzyme activity (Park et al. 2016. PubMed ID: 26506222). This variant is reported in 0.014% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-105207568-G-A). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Pathogenic

4.9

H;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.97

MVP

0.90

MPC

0.43

ClinPred

0.99

GERP RS

5.0

Varity_R

0.83

gMVP

0.96

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