4-88521773-G-C

Position:

• chr4-88521773-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001042616.3(PIGY):​c.17C>G​(p.Pro6Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 1,612,114 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (23 hom.)
• Consequence: PIGY NM_001042616.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.80

Genes affected

PIGY (HGNC:28213): (phosphatidylinositol glycan anchor biosynthesis class Y) The protein encoded by this gene is part of the GPI-N-acetylglucosaminyltransferase (GIP-GnT) complex which initiates the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is synthesized in the endoplasmic reticulum and serves as an anchor for many surface proteins. Proteins containing GPI anchors can have an important role in cell-cell interactions. The transcript for this gene is bicistronic. The downstream open reading frame encodes this GPI-GnT complex protein, while the upstream open reading frame encodes a protein with unknown function, as represented by GeneID:100996939. [provided by RefSeq, Aug 2012]

PYURF (HGNC:44317): (PIGY upstream open reading frame) The product of this gene, which is well-conserved, is encoded by the same bicistronic transcript that encodes phosphatidylinositol glycan anchor biosynthesis, class Y, but the two proteins are unrelated. This gene represents the protein encoded by the upstream open reading frame, while the protein encoded by the downstream open reading frame is represented by GeneID:84992. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 4-88521773-G-C is Benign according to our data. Variant chr4-88521773-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 425334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGY	NM_001042616.3	c.17C>G	p.Pro6Arg	missense_variant	2/2	ENST00000527353.2	NP_001036081.1
PYURF	NM_032906.5	c.*115C>G		3_prime_UTR_variant	2/2	ENST00000273968.5	NP_116295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGY	ENST00000527353.2	c.17C>G	p.Pro6Arg	missense_variant	2/2	6	NM_001042616.3	ENSP00000432688.1
PYURF	ENST00000273968	c.*115C>G		3_prime_UTR_variant	2/2	1	NM_032906.5	ENSP00000273968.4

Frequencies

GnomAD3 genomes AF: 0.00329 AC: 500 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00554

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00287 AC: 711 AN: 247600 Hom.: 2 AF XY: 0.00285 AC XY: 383 AN XY: 134324

Gnomad AFR exome AF: 0.000871

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.00333

GnomAD4 exome AF: 0.00480 AC: 7013 AN: 1459820 Hom.: 23 Cov.: 31 AF XY: 0.00471 AC XY: 3420 AN XY: 725948

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.000962

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00161

Gnomad4 NFE exome AF: 0.00592

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.00328 AC: 500 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00317 AC XY: 236 AN XY: 74466

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00554

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00407 Hom.: 3

Bravo AF: 0.00318

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00420 AC: 36

ExAC AF: 0.00278 AC: 337

EpiCase AF: 0.00469

EpiControl AF: 0.00577

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PIGY: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0090	T
MetaSVM	Uncertain	-0.20	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Vest4		0.53
MVP		0.20
MPC		0.28
ClinPred		0.044	T
GERP RS		4.7
Varity_R		0.53
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143548787; hg19: chr4-89442924; COSMIC: COSV105087948; COSMIC: COSV105087948;