14-104724434-C-T

Variant names:

• chr14-104724434-C-T
• rs1165633513
• NM_152328.5:c.164C>T

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.164C>T​(p.Thr55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000903 in 1,107,004 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: ADSS1 NM_152328.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• 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=0.24766341).

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.164C>T	p.Thr55Met	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.164C>T	p.Thr55Met	missense	Exon 1 of 13	ENSP00000331260.2	Q8N142-1
	ADSS1	ENST00000852145.1		c.164C>T	p.Thr55Met	missense	Exon 1 of 13	ENSP00000522204.1
	ADSS1	ENST00000710323.1		c.164C>T	p.Thr55Met	missense	Exon 1 of 13	ENSP00000518203.1	Q8N142-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.03e-7 AC: 1 AN: 1107004 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 524506

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

African (AFR) AF: 0.00 AC: 0 AN: 24016

American (AMR) AF: 0.00 AC: 0 AN: 10526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14460

East Asian (EAS) AF: 0.00 AC: 0 AN: 28130

South Asian (SAS) AF: 0.00 AC: 0 AN: 20662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2978

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 929238

Other (OTH) AF: 0.00 AC: 0 AN: 44376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

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	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.3
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.035
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.031	B
Vest4		0.16
MutPred		0.38		Loss of helix (P = 0.1299)
MVP		0.53
ClinPred		0.31	T
GERP RS		3.0
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
Mutation Taster		=78/22	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: rs1165633513; hg19: chr14-105190771;