NM_145167.3:c.1095T>A

Variant names:

• chr1-160030645-A-T
• rs12409352
• NM_145167.3:c.1095T>A

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict 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. F365V) has been classified as Uncertain significance.

• 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
• Publications: 24 publications found

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]

KCNJ10 Gene-Disease associations (from GenCC):

• EAST syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Pendred syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• enlarged vestibular aqueduct syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145167.3. 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
	PIGM	NM_145167.3	MANE Select	c.1095T>A	p.Phe365Leu	missense	Exon 1 of 1	NP_660150.1	Q9H3S5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGM	ENST00000368090.5	TSL:6 MANE Select	c.1095T>A	p.Phe365Leu	missense	Exon 1 of 1	ENSP00000357069.2	Q9H3S5
	KCNJ10	ENST00000509700.2	TSL:5	c.669+11189T>A		intron	N/A	ENSP00000491416.1	A0A1W2PPI0
	KCNJ10	ENST00000639408.2	TSL:5	c.587+9857T>A		intron	N/A	ENSP00000491635.1	A0A1W2PQC0

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

GnomAD2 exomes AF: 0.144 AC: 36184 AN: 251442 AF XY: 0.144

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 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

African (AFR) AF: 0.0259 AC: 866 AN: 33480

American (AMR) AF: 0.164 AC: 7340 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3791 AN: 26132

East Asian (EAS) AF: 0.0448 AC: 1779 AN: 39700

South Asian (SAS) AF: 0.102 AC: 8833 AN: 86252

European-Finnish (FIN) AF: 0.159 AC: 8520 AN: 53418

Middle Eastern (MID) AF: 0.0877 AC: 506 AN: 5768

European-Non Finnish (NFE) AF: 0.187 AC: 208469 AN: 1111864

Other (OTH) AF: 0.150 AC: 9038 AN: 60392

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

African (AFR) AF: 0.0324 AC: 1347 AN: 41582

American (AMR) AF: 0.137 AC: 2097 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 491 AN: 3472

East Asian (EAS) AF: 0.0372 AC: 193 AN: 5194

South Asian (SAS) AF: 0.0972 AC: 469 AN: 4824

European-Finnish (FIN) AF: 0.158 AC: 1675 AN: 10602

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12586 AN: 68006

Other (OTH) AF: 0.130 AC: 274 AN: 2110

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.51
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
Mutation Taster		=89/11	polymorphism (auto)

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