Genetic Variant ARGLU1:p.Thr63Pro (chr13-106567733-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018011.4(ARGLU1):c.187A>C(p.Thr63Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARGLU1
NM_018011.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

Variant links:

Genes affected

ARGLU1 (HGNC:25482): (arginine and glutamate rich 1) Enables cadherin binding activity. Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ARGLU1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0890539).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARGLU1	NM_018011.4 link	c.187A>C	p.Thr63Pro	missense_variant	Exon 1 of 4	ENST00000400198.8	NP_060481.3	Q9NWB6-1A0A024RDW4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARGLU1	ENST00000400198.8 link	c.187A>C	p.Thr63Pro	missense_variant	Exon 1 of 4	1	NM_018011.4	ENSP00000383059.3	Q9NWB6-1
ARGLU1	ENST00000472226.2 link	n.405A>C		non_coding_transcript_exon_variant	Exon 1 of 3	2
ARGLU1	ENST00000360629.3 link	n.-110A>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150246

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000244

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1456560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724684

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000665

AC:

AN:

150366

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73460

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.187A>C (p.T63P) alteration is located in exon 1 (coding exon 1) of the ARGLU1 gene. This alteration results from a A to C substitution at nucleotide position 187, causing the threonine (T) at amino acid position 63 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.022

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.55

M_CAP

Benign

0.015

MetaRNN

Benign

0.089

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.22

REVEL

Benign

0.026

Sift

Benign

0.16

Sift4G

Benign

0.36

Polyphen

0.014

Vest4

0.24

MutPred

0.25

Loss of phosphorylation at T63 (P = 0.0097);

MVP

0.12

MPC

1.8

ClinPred

0.17

GERP RS

0.18

Varity_R

0.13

gMVP

0.34

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over