10-97640962-A-T

Variant names:

• chr10-97640962-A-T
• rs1166227950
• NM_018425.4:c.220A>T

Variant summary

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

The NM_018425.4(PI4K2A):​c.220A>T​(p.Thr74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,519,758 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PI4K2A NM_018425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.756
• Publications: 0 publications found

Genes affected

PI4K2A (HGNC:30031): (phosphatidylinositol 4-kinase type 2 alpha) Phosphatidylinositolpolyphosphates (PtdInsPs) are centrally involved in many biologic processes, ranging from cell growth and organization of the actin cytoskeleton to endo- and exocytosis. PI4KII phosphorylates PtdIns at the D-4 position, an essential step in the biosynthesis of PtdInsPs (Barylko et al., 2001 [PubMed 11244087]).[supplied by OMIM, Mar 2008]

ENSG00000249967 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.05131355).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4K2A	NM_018425.4	MANE Select	c.220A>T	p.Thr74Ser	missense	Exon 1 of 9	NP_060895.1	Q9BTU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4K2A	ENST00000370631.4	TSL:1 MANE Select	c.220A>T	p.Thr74Ser	missense	Exon 1 of 9	ENSP00000359665.3	Q9BTU6
	ENSG00000249967	ENST00000370649.3	TSL:2	c.346-9979A>T		intron	N/A	ENSP00000359683.3	E9PAM4
	PI4K2A	ENST00000880060.1		c.220A>T	p.Thr74Ser	missense	Exon 1 of 10	ENSP00000550119.1

Frequencies

GnomAD3 genomes AF: 0.0000397 AC: 6 AN: 151264 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.0000515 AC: 6 AN: 116422 AF XY: 0.0000311

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000266

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: 0.0000110 AC: 15 AN: 1368494 Hom.: 0 Cov.: 32 AF XY: 0.00000741 AC XY: 5 AN XY: 674990

African (AFR) AF: 0.00 AC: 0 AN: 29398

American (AMR) AF: 0.000438 AC: 15 AN: 34226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24152

East Asian (EAS) AF: 0.00 AC: 0 AN: 34202

South Asian (SAS) AF: 0.00 AC: 0 AN: 77124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071926

Other (OTH) AF: 0.00 AC: 0 AN: 56996

GnomAD4 genome AF: 0.0000397 AC: 6 AN: 151264 Hom.: 0 Cov.: 31 AF XY: 0.0000542 AC XY: 4 AN XY: 73832

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

African (AFR) AF: 0.0000243 AC: 1 AN: 41204

American (AMR) AF: 0.000328 AC: 5 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67732

Other (OTH) AF: 0.00 AC: 0 AN: 2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000821565), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.76
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.044
Sift	Benign	0.49	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.13		Gain of glycosylation at T74 (P = 0.0255)
MVP		0.34
MPC		1.0
ClinPred		0.078	T
GERP RS		-0.47
PromoterAI		0.0061	Neutral
Varity_R		0.064
gMVP		0.19
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: rs1166227950; hg19: chr10-99400719;