NM_024989.4:c.*205G>C

Variant names:

• chr2-196841029-C-G
• rs59749746
• NM_024989.4:c.*205G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024989.4(PGAP1):​c.*205G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0925 in 542,230 control chromosomes in the GnomAD database, including 2,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1258 hom., cov: 32)
  • Exomes 𝑓: 0.084 (1717 hom.)
• Consequence: PGAP1 NM_024989.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.315
• Publications: 3 publications found

Genes affected

PGAP1 (HGNC:25712): (post-GPI attachment to proteins inositol deacylase 1) The protein encoded by this gene functions early in the glycosylphosphatidylinositol (GPI) biosynthetic pathway, catalyzing the inositol deacylation of GPI. The encoded protein is required for the production of GPI that can attach to proteins, and this may be an important factor in the transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi. Defects in this gene are a cause an autosomal recessive form of cognitive impairment. [provided by RefSeq, Jul 2017]

PGAP1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 42

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive spastic paraplegia type 67

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-196841029-C-G is Benign according to our data. Variant chr2-196841029-C-G is described in ClinVar as Benign. ClinVar VariationId is 1275518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024989.4. 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
	PGAP1	NM_024989.4	MANE Select	c.*205G>C		3_prime_UTR	Exon 27 of 27	NP_079265.2
	PGAP1	NM_001321099.2		c.*205G>C		3_prime_UTR	Exon 28 of 28	NP_001308028.1	Q75T13-2
	PGAP1	NM_001321100.2		c.*205G>C		3_prime_UTR	Exon 26 of 26	NP_001308029.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP1	ENST00000354764.9	TSL:1 MANE Select	c.*205G>C		3_prime_UTR	Exon 27 of 27	ENSP00000346809.3	Q75T13-1
	PGAP1	ENST00000423035.5	TSL:1	n.*2905G>C		non_coding_transcript_exon	Exon 28 of 28	ENSP00000415405.1	F8WD75
	PGAP1	ENST00000423035.5	TSL:1	n.*2905G>C		3_prime_UTR	Exon 28 of 28	ENSP00000415405.1	F8WD75

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17195 AN: 152080 Hom.: 1256 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0566

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0802

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0723

Gnomad OTH AF: 0.0976

GnomAD4 exome AF: 0.0845 AC: 32945 AN: 390032 Hom.: 1717 Cov.: 6 AF XY: 0.0871 AC XY: 17619 AN XY: 202356

African (AFR) AF: 0.206 AC: 2261 AN: 10960

American (AMR) AF: 0.0603 AC: 775 AN: 12848

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 1238 AN: 11530

East Asian (EAS) AF: 0.0562 AC: 1515 AN: 26968

South Asian (SAS) AF: 0.162 AC: 4349 AN: 26880

European-Finnish (FIN) AF: 0.0784 AC: 2249 AN: 28688

Middle Eastern (MID) AF: 0.146 AC: 253 AN: 1728

European-Non Finnish (NFE) AF: 0.0734 AC: 18208 AN: 248062

Other (OTH) AF: 0.0938 AC: 2097 AN: 22368

GnomAD4 genome AF: 0.113 AC: 17211 AN: 152198 Hom.: 1258 Cov.: 32 AF XY: 0.113 AC XY: 8374 AN XY: 74430

African (AFR) AF: 0.209 AC: 8664 AN: 41506

American (AMR) AF: 0.0665 AC: 1018 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 376 AN: 3468

East Asian (EAS) AF: 0.0568 AC: 295 AN: 5196

South Asian (SAS) AF: 0.166 AC: 799 AN: 4826

European-Finnish (FIN) AF: 0.0802 AC: 850 AN: 10594

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0723 AC: 4917 AN: 67992

Other (OTH) AF: 0.101 AC: 213 AN: 2112

Alfa AF: 0.102 Hom.: 129

Bravo AF: 0.115

Asia WGS AF: 0.123 AC: 429 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.77
DANN	Benign	0.43
PhyloP100		-0.32
Mutation Taster		=100/0	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: rs59749746; hg19: chr2-197705753;