Genetic Variant GPATCH1:p.Gly51Arg (chr19-33088211-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.151G>A(p.Gly51Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,603,448 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

GPATCH1
NM_018025.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.30

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, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPATCH1	NM_018025.3 link	c.151G>A	p.Gly51Arg	missense_variant	Exon 2 of 20	ENST00000170564.7	NP_060495.2	Q9BRR8
GPATCH1	XM_006723255.5 link	c.151G>A	p.Gly51Arg	missense_variant	Exon 2 of 14		XP_006723318.1
GPATCH1	NR_135270.2 link	n.164G>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.151G>A	p.Gly51Arg	missense_variant	Exon 2 of 20	1	NM_018025.3	ENSP00000170564.1		Q9BRR8
GPATCH1	ENST00000592165.1 link	n.151G>A		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000467632.1		K7EQ19

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

151070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

249968

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

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:

0.0000200

AC:

AN:

1452378

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

722922

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33074

American (AMR)

AF:

0.0000450

AC:

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.0000768

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

1104534

Other (OTH)

AF:

0.0000333

AC:

AN:

59994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000199

AC:

AN:

151070

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41094

American (AMR)

AF:

0.00

AC:

AN:

15078

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67902

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.151G>A (p.G51R) 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 151, causing the glycine (G) at amino acid position 51 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

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.36

MutationAssessor

Pathogenic

3.3

PhyloP100

7.3

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.90

Gain of MoRF binding (P = 0.0106);

MVP

0.87

MPC

0.65

ClinPred

0.99

GERP RS

4.4

Varity_R

0.90

gMVP

0.86

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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19-33088211-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