chr1-160030590-T-C

Variant names:

• chr1-160030590-T-C
• rs61747491
• NM_145167.3:c.1150A>G

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.1150A>G​(p.Asn384Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,130 control chromosomes in the GnomAD database, including 730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (329 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (401 hom.)
• Consequence: PIGM NM_145167.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.29
• Publications: 5 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: Ambry Genetics, G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=0.0018675625).
• BP6: Variant 1-160030590-T-C is Benign according to our data. Variant chr1-160030590-T-C is described in ClinVar as Benign. ClinVar VariationId is 1166403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 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.1150A>G	p.Asn384Asp	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.1150A>G	p.Asn384Asp	missense	Exon 1 of 1	ENSP00000357069.2	Q9H3S5
	KCNJ10	ENST00000509700.2	TSL:5	c.669+11244A>G		intron	N/A	ENSP00000491416.1	A0A1W2PPI0
	KCNJ10	ENST00000639408.2	TSL:5	c.587+9912A>G		intron	N/A	ENSP00000491635.1	A0A1W2PQC0

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6138 AN: 152168 Hom.: 329 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0162 AC: 4075 AN: 251446 AF XY: 0.0140

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0262

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.00810 AC: 11845 AN: 1461844 Hom.: 401 Cov.: 30 AF XY: 0.00810 AC XY: 5892 AN XY: 727236

African (AFR) AF: 0.139 AC: 4642 AN: 33470

American (AMR) AF: 0.0141 AC: 630 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0270 AC: 706 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0182 AC: 1571 AN: 86248

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53420

Middle Eastern (MID) AF: 0.0574 AC: 331 AN: 5768

European-Non Finnish (NFE) AF: 0.00275 AC: 3058 AN: 1111982

Other (OTH) AF: 0.0148 AC: 895 AN: 60396

GnomAD4 genome AF: 0.0403 AC: 6141 AN: 152286 Hom.: 329 Cov.: 32 AF XY: 0.0383 AC XY: 2856 AN XY: 74474

African (AFR) AF: 0.128 AC: 5314 AN: 41536

American (AMR) AF: 0.0214 AC: 327 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00316 AC: 215 AN: 68026

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0167 Hom.: 434

Bravo AF: 0.0462

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.129 AC: 567

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.0179 AC: 2171

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.00594

EpiControl AF: 0.00510

ClinVar

ClinVar submissions as Germline

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)
-	-	1	PIGM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.34
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.81	P
Vest4		0.30
MPC		1.0
ClinPred		0.036	T
GERP RS		5.3
Varity_R		0.57
gMVP		0.41
Mutation Taster		=76/24	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: rs61747491; hg19: chr1-160000380;