dbSNP rs185874005: PIGA:c.-63+13C>T (chrX-15335488-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002641.4(PIGA):c.-63+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 984,625 control chromosomes in the GnomAD database, including 15 homozygotes. There are 336 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 9 hom., 194 hem., cov: 25)

Exomes 𝑓: 0.00060 ( 6 hom. 142 hem. )

Consequence

PIGA
NM_002641.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.96

Publications

0 publications found

Variant links:

Genes affected

PIGA (HGNC:8957): (phosphatidylinositol glycan anchor biosynthesis class A) This gene encodes a protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI), the first intermediate in the biosynthetic pathway of GPI anchor. The GPI anchor is a glycolipid found on many blood cells and which serves to anchor proteins to the cell surface. Paroxysmal nocturnal hemoglobinuria, an acquired hematologic disorder, has been shown to result from mutations in this gene. Alternate splice variants have been characterized. A related pseudogene is located on chromosome 12. [provided by RefSeq, Jun 2010]

PIGA Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
multiple congenital anomalies-hypotonia-seizures syndrome 2
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ferro-cerebro-cutaneous syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
paroxysmal nocturnal hemoglobinuria
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

PIGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant X-15335488-G-A is Benign according to our data. Variant chrX-15335488-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00574 (651/113344) while in subpopulation AFR AF = 0.0198 (618/31288). AF 95% confidence interval is 0.0185. There are 9 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.

BS2

High AC in GnomAd4 at 651 Unknown,XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002641.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIGA	NM_002641.4	MANE Select	c.-63+13C>T	intron	N/A	NP_002632.1	P37287-1
PIGA	NM_001440789.1		c.-63+13C>T	intron	N/A	NP_001427718.1
PIGA	NM_001440790.1		c.13+13C>T	intron	N/A	NP_001427719.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PIGA	ENST00000333590.6	TSL:1 MANE Select	c.-63+13C>T	intron	N/A	ENSP00000369820.3	P37287-1
PIGA	ENST00000482148.6	TSL:5	c.-63+13C>T	intron	N/A	ENSP00000489528.1	P37287-2
PIGA	ENST00000634582.1	TSL:2	c.13+13C>T	intron	N/A	ENSP00000489540.1	P37287-3

Frequencies

GnomAD3 genomes

AF:

0.00573

AC:

649

AN:

113293

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0197

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00239

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000280

Gnomad SAS

AF:

0.000355

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00196

GnomAD2 exomes

AF:

0.000768

AC:

AN:

6514

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.000773

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000601

AC:

524

AN:

871281

Hom.:

Cov.:

AF XY:

0.000530

AC XY:

142

AN XY:

268083

show subpopulations

African (AFR)

AF:

0.0246

AC:

461

AN:

18712

American (AMR)

AF:

0.000950

AC:

AN:

8417

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12061

East Asian (EAS)

AF:

0.00

AC:

AN:

20710

South Asian (SAS)

AF:

0.00

AC:

AN:

24461

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19625

Middle Eastern (MID)

AF:

0.000290

AC:

AN:

3444

European-Non Finnish (NFE)

AF:

0.00000687

AC:

AN:

728028

Other (OTH)

AF:

0.00137

AC:

AN:

35823

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00574

AC:

651

AN:

113344

Hom.:

Cov.:

AF XY:

0.00547

AC XY:

194

AN XY:

35498

show subpopulations

African (AFR)

AF:

0.0198

AC:

618

AN:

31288

American (AMR)

AF:

0.00239

AC:

AN:

10901

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.000281

AC:

AN:

3562

South Asian (SAS)

AF:

0.000356

AC:

AN:

2809

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53369

Other (OTH)

AF:

0.00193

AC:

AN:

1551

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00669

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.1

(source)

DANN

Benign

0.76

PhyloP100

2.0

PromoterAI

0.017

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over