1-160030698-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_145167.3(PIGM):c.1042C>T(p.Pro348Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,062 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P348A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (33 hom.)
• Consequence: PIGM NM_145167.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.27

Genes affected

PIGM (HGNC:18858): (phosphatidylinositol glycan anchor biosynthesis class M) This gene encodes a transmembrane protein that is located in the endoplasmic reticulum and is involved in GPI-anchor biosynthesis. The glycosylphosphatidylinositol (GPI)-anchor is a glycolipid which contains three mannose molecules in its core backbone. The GPI-anchor is found on many blood cells and serves to anchor proteins to the cell surface. This gene encodes a mannosyltransferase, GPI-MT-I, that transfers the first mannose to GPI on the lumenal side of the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

KCNJ10 (HGNC:6256): (potassium inwardly rectifying channel subfamily J member 10) This gene encodes a member of the inward rectifier-type potassium channel family, characterized by having a greater tendency to allow potassium to flow into, rather than out of, a cell. The encoded protein may form a heterodimer with another potassium channel protein and may be responsible for the potassium buffering action of glial cells in the brain. Mutations in this gene have been associated with seizure susceptibility of common idiopathic generalized epilepsy syndromes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066707134).
• BP6: Variant 1-160030698-G-A is Benign according to our data. Variant chr1-160030698-G-A is described in ClinVar as [Benign]. Clinvar id is 2056194.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000591 (90/152322) while in subpopulation SAS AF= 0.0182 (88/4826). AF 95% confidence interval is 0.0152. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGM	NM_145167.3	c.1042C>T	p.Pro348Ser	missense_variant	1/1	ENST00000368090.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGM	ENST00000368090.5	c.1042C>T	p.Pro348Ser	missense_variant	1/1		NM_145167.3	P1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152204 Hom.: 0 Cov.: 32

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: 0.0182

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00208 AC: 522 AN: 251410 Hom.: 8 AF XY: 0.00279 AC XY: 379 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0169

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00108 AC: 1576 AN: 1461740 Hom.: 33 Cov.: 32 AF XY: 0.00158 AC XY: 1151 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0175

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.00241 AC: 293

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.039
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.27
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.025	D
Polyphen		0.25	B
Vest4		0.54
MutPred		0.69		Gain of MoRF binding (P = 0.0511);
MVP		0.57
MPC		1.0
ClinPred		0.14	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs201082832; hg19: chr1-160000488;