Genetic Variant GPATCH1:p.Arg48Gln (chr19-33088203-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_018025.3(GPATCH1):c.143G>A(p.Arg48Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000288 in 1,596,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

GPATCH1
NM_018025.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.14

Publications

4 publications found

Variant links:

Genes affected

GPATCH1 (HGNC:24658): (G-patch domain containing 1) Predicted to enable RNA binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Part of catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

GPATCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPATCH1	NM_018025.3 link	c.143G>A	p.Arg48Gln	missense_variant	Exon 2 of 20	ENST00000170564.7	NP_060495.2	Q9BRR8
GPATCH1	XM_006723255.5 link	c.143G>A	p.Arg48Gln	missense_variant	Exon 2 of 14		XP_006723318.1
GPATCH1	NR_135270.2 link	n.156G>A		non_coding_transcript_exon_variant	Exon 2 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPATCH1	ENST00000170564.7 link	c.143G>A	p.Arg48Gln	missense_variant	Exon 2 of 20	1	NM_018025.3	ENSP00000170564.1		Q9BRR8
GPATCH1	ENST00000592165.1 link	n.143G>A		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000467632.1		K7EQ19

Frequencies

GnomAD3 genomes

AF:

0.0000406

AC:

AN:

147848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000749

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:

0.0000444

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000320

AC:

AN:

250168

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.000371

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000269

AC:

AN:

1448280

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

721074

show subpopulations

African (AFR)

AF:

0.000364

AC:

AN:

32956

American (AMR)

AF:

0.00

AC:

AN:

44342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25920

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39346

South Asian (SAS)

AF:

0.00

AC:

AN:

85558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

1101670

Other (OTH)

AF:

0.0000837

AC:

AN:

59738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000473

AC:

AN:

147966

Hom.:

Cov.:

AF XY:

0.0000558

AC XY:

AN XY:

71704

show subpopulations

African (AFR)

AF:

0.0000996

AC:

AN:

40170

American (AMR)

AF:

0.00

AC:

AN:

14516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5010

South Asian (SAS)

AF:

0.00

AC:

AN:

4666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000444

AC:

AN:

67520

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000502

Hom.:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 07, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.143G>A (p.R48Q) alteration is located in exon 2 (coding exon 2) of the GPATCH1 gene. This alteration results from a G to A substitution at nucleotide position 143, causing the arginine (R) at amino acid position 48 to be replaced by a glutamine (Q). 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

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.012

MutationAssessor

Pathogenic

3.6

PhyloP100

9.1

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MVP

0.81

MPC

0.62

ClinPred

0.98

GERP RS

5.4

Varity_R

0.57

gMVP

0.73

Mutation Taster

=10/90

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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19-33088203-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over