chr15-55355378-A-G

Variant names:

• chr15-55355378-A-G
• rs2056056414
• NM_004855.5:c.1611A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_004855.5(PIGB):​c.1611A>G​(p.Ile537Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I537L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PIGB NM_004855.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.423
• Publications: 0 publications found

Genes affected

PIGB (HGNC:8959): (phosphatidylinositol glycan anchor biosynthesis class B) 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 found on many blood cells and serves to anchor proteins to the cell surface. This gene is thought to encode a member of a family of dolichol-phosphate-mannose (Dol-P-Man) dependent mannosyltransferases. [provided by RefSeq, Jul 2008]

CCPG1 (HGNC:24227): (cell cycle progression 1) Involved in positive regulation of cell cycle and positive regulation of cell population proliferation. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF4-CCPG1 (HGNC:43019): (DNAAF4-CCPG1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring dyslexia susceptibility 1 candidate 1 (DYX1C1) and cell cycle progression 1 (CCPG1) genes on chromosome 15. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-55355378-A-G is Pathogenic according to our data. Variant chr15-55355378-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 976715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24001276). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004855.5. 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
	PIGB	NM_004855.5	MANE Select	c.1611A>G	p.Ile537Met	missense	Exon 12 of 12	NP_004846.4
	CCPG1	NM_001204450.2	MANE Select	c.*842T>C		3_prime_UTR	Exon 9 of 9	NP_001191379.1	Q9ULG6-5
	CCPG1	NM_004748.6		c.*4121T>C		3_prime_UTR	Exon 8 of 8	NP_004739.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGB	ENST00000164305.10	TSL:1 MANE Select	c.1611A>G	p.Ile537Met	missense	Exon 12 of 12	ENSP00000164305.5	Q92521
	CCPG1	ENST00000442196.8	TSL:2 MANE Select	c.*842T>C		3_prime_UTR	Exon 9 of 9	ENSP00000403400.3	Q9ULG6-5
	CCPG1	ENST00000310958.10	TSL:1	c.*4121T>C		3_prime_UTR	Exon 8 of 8	ENSP00000311656.6	Q9ULG6-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459714 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726294

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110388

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy, 80 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.42
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.16	T
Polyphen		0.091	B
Vest4		0.33
MutPred		0.54		Loss of catalytic residue at I537 (P = 0.0232)
MVP		0.59
MPC		0.23
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.30
gMVP		0.63
Mutation Taster		=69/31	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2056056414; hg19: chr15-55647576;