rs34001453

Variant names:

• chr1-172441947-G-A
• rs34001453
• NM_153747.2:c.676C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-172441947-G-A
• chr1-172441947-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_153747.2(PIGC):​c.676C>T​(p.Arg226Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,614,166 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R226Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (77 hom.)
• Consequence: PIGC NM_153747.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.565
• Publications: 9 publications found

Genes affected

PIGC (HGNC:8960): (phosphatidylinositol glycan anchor biosynthesis class C) This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) lipid anchor biosynthesis. The GPI lipid anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. The encoded protein is one subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. Two alternatively spliced transcripts that encode the same protein have been found for this gene. A pseudogene on chromosome 11 has also been characterized. [provided by RefSeq, Jul 2008]

C1orf105 (HGNC:29591): (chromosome 1 open reading frame 105)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM1: In a chain Phosphatidylinositol N-acetylglucosaminyltransferase subunit C (size 296) in uniprot entity PIGC_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_153747.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.004669845).
• BP6: Variant 1-172441947-G-A is Benign according to our data. Variant chr1-172441947-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 769251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153747.2. 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
	PIGC	NM_153747.2	MANE Select	c.676C>T	p.Arg226Trp	missense	Exon 2 of 2	NP_714969.1	Q92535
	C1orf105	NM_139240.4	MANE Select	c.22-3126G>A		intron	N/A	NP_640333.3
	PIGC	NM_002642.4		c.676C>T	p.Arg226Trp	missense	Exon 2 of 2	NP_002633.1	Q92535

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGC	ENST00000344529.5	TSL:1 MANE Select	c.676C>T	p.Arg226Trp	missense	Exon 2 of 2	ENSP00000356701.3	Q92535
	C1orf105	ENST00000367727.9	TSL:1 MANE Select	c.22-3126G>A		intron	N/A	ENSP00000356700.4	O95561
	PIGC	ENST00000484368.1	TSL:1	n.96+2041C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00613 AC: 933 AN: 152182 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00565 AC: 1421 AN: 251346 AF XY: 0.00571

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00992

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00894 AC: 13070 AN: 1461866 Hom.: 77 Cov.: 40 AF XY: 0.00862 AC XY: 6272 AN XY: 727240

African (AFR) AF: 0.00257 AC: 86 AN: 33480

American (AMR) AF: 0.00275 AC: 123 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26134

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

South Asian (SAS) AF: 0.00109 AC: 94 AN: 86258

European-Finnish (FIN) AF: 0.00378 AC: 202 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0108 AC: 11969 AN: 1111990

Other (OTH) AF: 0.00942 AC: 569 AN: 60394

GnomAD4 genome AF: 0.00612 AC: 932 AN: 152300 Hom.: 5 Cov.: 32 AF XY: 0.00541 AC XY: 403 AN XY: 74470

African (AFR) AF: 0.00236 AC: 98 AN: 41572

American (AMR) AF: 0.00445 AC: 68 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0104 AC: 705 AN: 68024

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00929 Hom.: 52

Bravo AF: 0.00605

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0110 AC: 95

ExAC AF: 0.00568 AC: 690

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0111

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.56
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.068
Sift	Benign	0.19	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.20
MVP		0.51
MPC		0.13
ClinPred		0.0033	T
GERP RS		1.4
Varity_R		0.050
gMVP		0.51
Mutation Taster		=100/0	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: rs34001453; hg19: chr1-172411087; COSMIC: COSV99033064; COSMIC: COSV99033064;