Genetic Variant NM_018025.3:c.163G>A (chr19-33088223-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018025.3(GPATCH1):c.163G>A(p.Gly55Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,606,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GPATCH1
NM_018025.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.14

Publications

0 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: 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPATCH1	NM_018025.3 link	c.163G>A	p.Gly55Arg	missense_variant	Exon 2 of 20	ENST00000170564.7	NP_060495.2	Q9BRR8
GPATCH1	XM_006723255.5 link	c.163G>A	p.Gly55Arg	missense_variant	Exon 2 of 14		XP_006723318.1
GPATCH1	NR_135270.2 link	n.176G>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.163G>A	p.Gly55Arg	missense_variant	Exon 2 of 20	1	NM_018025.3	ENSP00000170564.1		Q9BRR8
GPATCH1	ENST00000592165.1 link	n.163G>A		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000467632.1		K7EQ19

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000800

AC:

AN:

250108

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000131

AC:

AN:

1454638

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

724092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33114

American (AMR)

AF:

0.00

AC:

AN:

44382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

1106590

Other (OTH)

AF:

0.0000166

AC:

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151504

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41232

American (AMR)

AF:

0.00

AC:

AN:

15162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.163G>A (p.G55R) 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 163, causing the glycine (G) at amino acid position 55 to be replaced by an arginine (R). 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

0.98

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.6

PhyloP100

9.1

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.87

Gain of MoRF binding (P = 0.0073);

MVP

0.94

MPC

0.64

ClinPred

1.0

GERP RS

5.4

Varity_R

0.92

gMVP

0.84

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_018025.3:c.163G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over