12-19269884-A-G

Variant names:

• chr12-19269884-A-G
• NM_001256470.2:c.826A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001256470.2(PLEKHA5):​c.826A>G​(p.Arg276Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLEKHA5 NM_001256470.2 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.13
• Publications: 0 publications found

Genes affected

PLEKHA5 (HGNC:30036): (pleckstrin homology domain containing A5) Predicted to enable phosphatidylinositol phosphate binding activity. Predicted to act upstream of or within reproductive system development. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA5	NM_001256470.2	c.826A>G	p.Arg276Gly	missense_variant, splice_region_variant	Exon 9 of 32	ENST00000429027.7	NP_001243399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA5	ENST00000429027.7	c.826A>G	p.Arg276Gly	missense_variant, splice_region_variant	Exon 9 of 32	1	NM_001256470.2	ENSP00000404296.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1334436 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 670254

African (AFR) AF: 0.00 AC: 0 AN: 30964

American (AMR) AF: 0.00 AC: 0 AN: 43194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 39046

South Asian (SAS) AF: 0.00 AC: 0 AN: 82106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 999004

Other (OTH) AF: 0.00 AC: 0 AN: 56120

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.826A>G (p.R276G) alteration is located in exon 9 (coding exon 9) of the PLEKHA5 gene. This alteration results from a A to G substitution at nucleotide position 826, causing the arginine (R) at amino acid position 276 to be replaced by a glycine (G). 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	0.62
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;T;.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T;D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M;.;M;M;.;.
PhyloP100		8.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.056	T;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.71, 0.99	.;.;P;D;.;.
Vest4		0.59
MutPred		0.49		Gain of catalytic residue at E272 (P = 0.0137);.;Gain of catalytic residue at E272 (P = 0.0137);Gain of catalytic residue at E272 (P = 0.0137);.;.;
MVP		0.43
MPC		1.0
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.69
gMVP		0.34
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: 1

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

Other links and lift over

hg19: chr12-19422818;