chr19-33088155-T-C

Variant names:

• chr19-33088155-T-C
• rs1972554033
• NM_018025.3:c.95T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018025.3(GPATCH1):​c.95T>C​(p.Ile32Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 974,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GPATCH1 NM_018025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16266751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPATCH1	NM_018025.3	c.95T>C	p.Ile32Thr	missense_variant	Exon 2 of 20	ENST00000170564.7	NP_060495.2
GPATCH1	XM_006723255.5	c.95T>C	p.Ile32Thr	missense_variant	Exon 2 of 14		XP_006723318.1
GPATCH1	NR_135270.2	n.108T>C		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	c.95T>C	p.Ile32Thr	missense_variant	Exon 2 of 20	1	NM_018025.3	ENSP00000170564.1
GPATCH1	ENST00000592165.1	n.95T>C		non_coding_transcript_exon_variant	Exon 2 of 10	5		ENSP00000467632.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 140380 Hom.: 0 Cov.: 28

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 6 AN: 974816 Hom.: 0 Cov.: 25 AF XY: 0.0000100 AC XY: 5 AN XY: 497804

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000882 AC: 2 AN: 22674

American (AMR) AF: 0.00 AC: 0 AN: 30964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19426

East Asian (EAS) AF: 0.00 AC: 0 AN: 31354

South Asian (SAS) AF: 0.0000147 AC: 1 AN: 68042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 711440

Other (OTH) AF: 0.0000723 AC: 3 AN: 41502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 140380 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 67794

African (AFR) AF: 0.00 AC: 0 AN: 38310

American (AMR) AF: 0.00 AC: 0 AN: 13720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3346

East Asian (EAS) AF: 0.00 AC: 0 AN: 4380

South Asian (SAS) AF: 0.00 AC: 0 AN: 4178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8300

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65040

Other (OTH) AF: 0.00 AC: 0 AN: 1944

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.95T>C (p.I32T) alteration is located in exon 2 (coding exon 2) of the GPATCH1 gene. This alteration results from a T to C substitution at nucleotide position 95, causing the isoleucine (I) at amino acid position 32 to be replaced by a threonine (T). 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	0.25
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.5
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.053
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.028	D
Polyphen		0.0030	B
Vest4		0.15
MutPred		0.39		Gain of glycosylation at I32 (P = 0.0141);
MVP		0.32
MPC		0.17
ClinPred		0.75	D
GERP RS		3.2
Varity_R		0.29
gMVP		0.27
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1972554033; hg19: chr19-33579061;