Genetic Variant ADSS1:p.Met1? (chr14-104729895-G-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 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

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

myopathy, distal, 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ADSS1 links:

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ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD2 exomes

AF:

0.0000145

AC:

AN:

137748

AF XY:

0.0000273

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 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

African (AFR)

AF:

0.00

AC:

AN:

28828

American (AMR)

AF:

0.00

AC:

AN:

33200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23988

East Asian (EAS)

AF:

0.00

AC:

AN:

34826

South Asian (SAS)

AF:

0.00

AC:

AN:

76842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44056

Middle Eastern (MID)

AF:

0.000219

AC:

AN:

4570

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057586

Other (OTH)

AF:

0.00

AC:

AN:

56042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.00804

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

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

PhyloP100

1.9

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

PromoterAI

0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.22

Mutation Taster

=148/52

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over