19-33093438-G-A

Variant names:

• chr19-33093438-G-A
• rs374456620
• NM_018025.3:c.374G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018025.3(GPATCH1):​c.374G>A​(p.Arg125Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GPATCH1 NM_018025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03783837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPATCH1	NM_018025.3	c.374G>A	p.Arg125Gln	missense_variant	Exon 4 of 20	ENST00000170564.7	NP_060495.2
GPATCH1	XM_006723255.5	c.374G>A	p.Arg125Gln	missense_variant	Exon 4 of 14		XP_006723318.1
GPATCH1	NR_135270.2	n.387G>A		non_coding_transcript_exon_variant	Exon 4 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPATCH1	ENST00000170564.7	c.374G>A	p.Arg125Gln	missense_variant	Exon 4 of 20	1	NM_018025.3	ENSP00000170564.1
GPATCH1	ENST00000592165.1	n.295-2324G>A		intron_variant	Intron 3 of 9	5		ENSP00000467632.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

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

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251472 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000123

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727178

African (AFR) AF: 0.000299 AC: 10 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111854

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74406

African (AFR) AF: 0.000193 AC: 8 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374G>A (p.R125Q) alteration is located in exon 4 (coding exon 4) of the GPATCH1 gene. This alteration results from a G to A substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 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	Benign	0.064
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.016
Sift	Benign	0.23	T
Sift4G	Benign	0.35	T
Polyphen		0.017	B
Vest4		0.097
MVP		0.29
MPC		0.15
ClinPred		0.13	T
GERP RS		2.4
Varity_R		0.070
gMVP		0.44
Mutation Taster		=93/7	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: rs374456620; hg19: chr19-33584344;