14-104724300-GC-GCC

Variant names:

• chr14-104724300-G-GC
• rs781559734
• NM_152328.5:c.36dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_152328.5(ADSS1):​c.36dupC​(p.Gly13ArgfsTer99) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,081,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ADSS1 NM_152328.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.888
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• myopathy, distal, 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152328.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSS1	NM_152328.5	MANE Select	c.36dupC	p.Gly13ArgfsTer99	frameshift	Exon 1 of 13	NP_689541.1	Q8N142-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSS1	ENST00000330877.7	TSL:1 MANE Select	c.36dupC	p.Gly13ArgfsTer99	frameshift	Exon 1 of 13	ENSP00000331260.2	Q8N142-1
	ADSS1	ENST00000852145.1		c.36dupC	p.Gly13ArgfsTer99	frameshift	Exon 1 of 13	ENSP00000522204.1
	ADSS1	ENST00000710323.1		c.36dupC	p.Gly13ArgfsTer99	frameshift	Exon 1 of 13	ENSP00000518203.1	Q8N142-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 3436 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000148 AC: 16 AN: 1081032 Hom.: 0 Cov.: 30 AF XY: 0.0000176 AC XY: 9 AN XY: 510964

African (AFR) AF: 0.00 AC: 0 AN: 22790

American (AMR) AF: 0.00 AC: 0 AN: 8294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14216

East Asian (EAS) AF: 0.000114 AC: 3 AN: 26392

South Asian (SAS) AF: 0.0000508 AC: 1 AN: 19704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2912

European-Non Finnish (NFE) AF: 0.0000120 AC: 11 AN: 918602

Other (OTH) AF: 0.0000230 AC: 1 AN: 43454

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Myopathy, distal, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.89

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

Other links and lift over

dbSNP: rs781559734; hg19: chr14-105190637;