rs150558753

Variant names:

• chr14-104729895-G-C
• rs150558753
• ENST00000332972.9:c.3G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-104729895-G-C
• chr14-104729895-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.94
• Publications: 2 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 7 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199165.2. 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.193-5125G>C		intron	N/A	NP_689541.1	Q8N142-1
	ADSS1	NM_199165.2		c.3G>C	p.Met1?	start_lost	Exon 1 of 13	NP_954634.1	B3KTV4
	ADSS1	NM_001320424.1		c.-725G>C		5_prime_UTR	Exon 1 of 13	NP_001307353.1	Q8N142

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADSS1	ENST00000332972.9	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 13	ENSP00000333019.5	Q8N142-2
	ADSS1	ENST00000330877.7	TSL:1 MANE Select	c.193-5125G>C		intron	N/A	ENSP00000331260.2	Q8N142-1
	ADSS1	ENST00000852145.1		c.193-5125G>C		intron	N/A	ENSP00000522204.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000145 AC: 2 AN: 137748 AF XY: 0.0000273

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1359938 Hom.: 0 Cov.: 35 AF XY: 0.00000150 AC XY: 1 AN XY: 666308

African (AFR) AF: 0.00 AC: 0 AN: 28828

American (AMR) AF: 0.00 AC: 0 AN: 33200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23988

East Asian (EAS) AF: 0.00 AC: 0 AN: 34826

South Asian (SAS) AF: 0.00 AC: 0 AN: 76842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44056

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4570

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057586

Other (OTH) AF: 0.00 AC: 0 AN: 56042

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00804 AC: 33

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.89
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.9
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.083
Sift	Benign	0.055	T
Sift4G	Benign	0.29	T
Polyphen		0.0030	B
Vest4		0.19
MutPred		0.91		Gain of catalytic residue at S5 (P = 0)
MVP		0.14
ClinPred		0.19	T
GERP RS		0.16
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.22
Mutation Taster		=148/52	polymorphism

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

Other links and lift over

dbSNP: rs150558753; hg19: chr14-105196232; COSMIC: COSV58273870;