chr19-33109992-G-A

Variant names:

• chr19-33109992-G-A
• rs201456156
• NM_018025.3:c.1561G>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.1561G>A​(p.Val521Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,611,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: GPATCH1 NM_018025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71
• Publications: 2 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=0.011923432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPATCH1	NM_018025.3	c.1561G>A	p.Val521Ile	missense_variant	Exon 11 of 20	ENST00000170564.7	NP_060495.2
GPATCH1	XM_006723255.5	c.1561G>A	p.Val521Ile	missense_variant	Exon 11 of 14		XP_006723318.1
GPATCH1	NR_135270.2	n.1574G>A		non_coding_transcript_exon_variant	Exon 11 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPATCH1	ENST00000170564.7	c.1561G>A	p.Val521Ile	missense_variant	Exon 11 of 20	1	NM_018025.3	ENSP00000170564.1
GPATCH1	ENST00000590062.1	n.116G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2
GPATCH1	ENST00000592165.1	n.*1017G>A		downstream_gene_variant		5		ENSP00000467632.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000682 AC: 17 AN: 249180 AF XY: 0.0000371

Gnomad AFR exome AF: 0.000925

Gnomad AMR exome AF: 0.0000292

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: 0.0000487 AC: 71 AN: 1459256 Hom.: 0 Cov.: 32 AF XY: 0.0000386 AC XY: 28 AN XY: 725610

African (AFR) AF: 0.00165 AC: 55 AN: 33428

American (AMR) AF: 0.0000900 AC: 4 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110472

Other (OTH) AF: 0.000133 AC: 8 AN: 60258

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74504

African (AFR) AF: 0.00106 AC: 44 AN: 41584

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.000366

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1561G>A (p.V521I) alteration is located in exon 11 (coding exon 11) of the GPATCH1 gene. This alteration results from a G to A substitution at nucleotide position 1561, causing the valine (V) at amino acid position 521 to be replaced by an isoleucine (I). 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	0.071
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.072
Sift	Benign	0.42	T
Sift4G	Benign	0.23	T
Polyphen		0.078	B
Vest4		0.098
MVP		0.21
MPC		0.10
ClinPred		0.024	T
GERP RS		5.7
Varity_R		0.018
gMVP		0.098
Mutation Taster		=94/6	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: rs201456156; hg19: chr19-33600898;