rs996618149

Variant names:

• chr14-104724347-C-T
• rs996618149
• NM_152328.5:c.77C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-104724347-C-T
• chr14-104724347-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152328.5(ADSS1):​c.77C>T​(p.Ala26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,242,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A26A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ADSS1 NM_152328.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.130
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10270417).

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.77C>T	p.Ala26Val	missense	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.77C>T	p.Ala26Val	missense	Exon 1 of 13	ENSP00000331260.2	Q8N142-1
	ADSS1	ENST00000852145.1		c.77C>T	p.Ala26Val	missense	Exon 1 of 13	ENSP00000522204.1
	ADSS1	ENST00000710323.1		c.77C>T	p.Ala26Val	missense	Exon 1 of 13	ENSP00000518203.1	Q8N142-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1090648 Hom.: 0 Cov.: 30 AF XY: 0.00000582 AC XY: 3 AN XY: 515768

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000431 AC: 1 AN: 23176

American (AMR) AF: 0.00 AC: 0 AN: 8468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14334

East Asian (EAS) AF: 0.00 AC: 0 AN: 26824

South Asian (SAS) AF: 0.00 AC: 0 AN: 19836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2932

European-Non Finnish (NFE) AF: 0.00000217 AC: 2 AN: 921168

Other (OTH) AF: 0.00 AC: 0 AN: 43740

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00109982), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.13
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.061
Sift	Benign	0.28	T
Sift4G	Benign	0.54	T
Polyphen		0.55	P
Vest4		0.088
MutPred		0.18		Gain of MoRF binding (P = 0.1011)
MVP		0.33
ClinPred		0.25	T
GERP RS		0.71
PromoterAI		0.039	Neutral
Varity_R		0.067
Mutation Taster		=89/11	polymorphism

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: rs996618149; hg19: chr14-105190684;