1-160030645-A-T

Position:

• chr1-160030645-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_145167.3(PIGM):​c.1095T>A​(p.Phe365Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,614,028 control chromosomes in the GnomAD database, including 24,426 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1635 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22791 hom.)
• Consequence: PIGM NM_145167.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.513

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019436479).
• BP6: Variant 1-160030645-A-T is Benign according to our data. Variant chr1-160030645-A-T is described in ClinVar as [Benign]. Clinvar id is 1164402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGM	NM_145167.3	c.1095T>A	p.Phe365Leu	missense_variant	1/1	ENST00000368090.5	NP_660150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGM	ENST00000368090.5	c.1095T>A	p.Phe365Leu	missense_variant	1/1		NM_145167.3	ENSP00000357069	P1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19372 AN: 152182 Hom.: 1635 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.0980

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.144 AC: 36184 AN: 251442 Hom.: 3103 AF XY: 0.144 AC XY: 19567 AN XY: 135900

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.0327

Gnomad SAS exome AF: 0.0992

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.170 AC: 249142 AN: 1461728 Hom.: 22791 Cov.: 33 AF XY: 0.169 AC XY: 122626 AN XY: 727186

Gnomad4 AFR exome AF: 0.0259

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.0448

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.127 AC: 19379 AN: 152300 Hom.: 1635 Cov.: 32 AF XY: 0.125 AC XY: 9304 AN XY: 74462

Gnomad4 AFR AF: 0.0324

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.0372

Gnomad4 SAS AF: 0.0972

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.130

Alfa AF: 0.171 Hom.: 1827

Bravo AF: 0.120

TwinsUK AF: 0.182 AC: 675

ALSPAC AF: 0.192 AC: 740

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.178 AC: 1528

ExAC AF: 0.140 AC: 17052

Asia WGS AF: 0.0850 AC: 296 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -

Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.7
DANN	Benign	0.90
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.13	P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.069
Sift	Benign	0.35	T
Sift4G	Benign	0.91	T
Polyphen		0.11	B
Vest4		0.092
MutPred		0.27		Loss of catalytic residue at F365 (P = 0.0226);
MPC		0.50
ClinPred		0.0053	T
GERP RS		-0.83
Varity_R		0.21
gMVP		0.34

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: rs12409352; hg19: chr1-160000435; COSMIC: COSV63635661;