rs559454746

Variant names:

• chr14-104741972-CA-C
• rs559454746
• NM_152328.5:c.919delA

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS1_Supporting

The NM_152328.5(ADSS1):​c.919delA​(p.Ile307SerfsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.00018 in 1,613,206 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: ADSS1 NM_152328.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-104741972-CA-C is Pathogenic according to our data. Variant chr14-104741972-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 243026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00019 (278/1460870) while in subpopulation EAS AF= 0.00693 (275/39700). AF 95% confidence interval is 0.00625. There are 2 homozygotes in gnomad4_exome. There are 125 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADSS1	NM_152328.5	c.919delA	p.Ile307SerfsTer25	frameshift_variant	Exon 9 of 13	ENST00000330877.7	NP_689541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADSS1	ENST00000330877.7	c.919delA	p.Ile307SerfsTer25	frameshift_variant	Exon 9 of 13	1	NM_152328.5	ENSP00000331260.2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00250

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: 0.0000877 AC: 22 AN: 250874 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000190 AC: 278 AN: 1460870 Hom.: 2 Cov.: 31 AF XY: 0.000172 AC XY: 125 AN XY: 726750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00693

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 8 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, distal, 5 Pathogenic:4

Jul 20, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29300372). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 1.00 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYH7 related disorder (ClinVar ID: VCV001329405 /PMID: 25132132 /3billion dataset).Different missense changes at the same codon (p.Glu894Gln, p.Glu894Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042922 /PMID: 15358028, 24793961). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADSS1 c.1048delA (p.Ile350SerfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 282242 control chromosomes. c.1048delA has been reported in the literature in multiple individuals affected with Myopathy, Distal, 5, including as a compound heterozygous genotype (e.g. Park_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28268051). ClinVar contains an entry for this variant (Variation ID: 243026). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jan 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ile350Serfs*25) in the ADSSL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADSSL1 are known to be pathogenic (PMID: 26506222). This variant is present in population databases (rs559454746, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with autosomal recessive distal myopathy (PMID: 26506222, 27868399, 28268051). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 243026). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs559454746; hg19: chr14-105208309; COSMIC: COSV58273814; COSMIC: COSV58273814;