11-62338014-G-T

Variant names:

• chr11-62338014-G-T
• rs746830715
• NM_001083926.2:c.37G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001083926.2(ASRGL1):​c.37G>T​(p.Gly13Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G13S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASRGL1 NM_001083926.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.902
• Publications: 0 publications found

Genes affected

ASRGL1 (HGNC:16448): (asparaginase and isoaspartyl peptidase 1) Enables asparaginase activity and beta-aspartyl-peptidase activity. Involved in asparagine catabolic process via L-aspartate. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ASRGL1 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ENSG00000255118 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083926.2. 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
	ASRGL1	NM_001083926.2	MANE Select	c.37G>T	p.Gly13Cys	missense	Exon 2 of 7	NP_001077395.1	A0A024R573
	ASRGL1	NM_025080.4		c.37G>T	p.Gly13Cys	missense	Exon 2 of 7	NP_079356.3
	ASRGL1	NM_001441216.1		c.37G>T	p.Gly13Cys	missense	Exon 2 of 5	NP_001428145.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASRGL1	ENST00000415229.6	TSL:1 MANE Select	c.37G>T	p.Gly13Cys	missense	Exon 2 of 7	ENSP00000400057.2	Q7L266-1
	ASRGL1	ENST00000301776.9	TSL:1	c.37G>T	p.Gly13Cys	missense	Exon 2 of 7	ENSP00000301776.5	Q7L266-1
	ASRGL1	ENST00000628829.2	TSL:1	c.37G>T	p.Gly13Cys	missense	Exon 2 of 6	ENSP00000486943.1	E9PJK6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454242 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722754

⚠️ 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: 33418

American (AMR) AF: 0.00 AC: 0 AN: 43534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 39456

South Asian (SAS) AF: 0.00 AC: 0 AN: 84834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108970

Other (OTH) AF: 0.00 AC: 0 AN: 60098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.90
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.47
Sift	Benign	0.085	T
Sift4G	Benign	0.064	T
Polyphen		0.78	P
Vest4		0.28
MutPred		0.92		Loss of disorder (P = 0.0103)
MVP		0.90
MPC		0.36
ClinPred		0.99	D
GERP RS		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.75
Mutation Taster		=79/21	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: rs746830715; hg19: chr11-62105486;