1-172390640-A-G

Variant names:

• chr1-172390640-A-G
• rs2227199
• NM_015569.5:c.2522+1831A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015569.5(DNM3):​c.2522+1831A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 152,196 control chromosomes in the GnomAD database, including 20,308 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (20308 hom., cov: 33)
• Consequence: DNM3 NM_015569.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• Publications: 5 publications found

Genes affected

DNM3 (HGNC:29125): (dynamin 3) This gene encodes a member of a family of guanosine triphosphate (GTP)-binding proteins that associate with microtubules and are involved in vesicular transport. The encoded protein functions in the development of megakaryocytes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

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]

PIGC Gene-Disease associations (from GenCC):

• glycosylphosphatidylinositol biosynthesis defect 16

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM3	NM_015569.5	c.2522+1831A>G		intron_variant	Intron 20 of 20	ENST00000627582.3	NP_056384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM3	ENST00000627582.3	c.2522+1831A>G		intron_variant	Intron 20 of 20	1	NM_015569.5	ENSP00000486701.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72375 AN: 152078 Hom.: 20305 Cov.: 33

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.528

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.476 AC: 72399 AN: 152196 Hom.: 20308 Cov.: 33 AF XY: 0.482 AC XY: 35865 AN XY: 74392

African (AFR) AF: 0.167 AC: 6922 AN: 41544

American (AMR) AF: 0.634 AC: 9703 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1914 AN: 3470

East Asian (EAS) AF: 0.870 AC: 4516 AN: 5188

South Asian (SAS) AF: 0.565 AC: 2726 AN: 4822

European-Finnish (FIN) AF: 0.547 AC: 5786 AN: 10580

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.573 AC: 38947 AN: 67980

Other (OTH) AF: 0.532 AC: 1125 AN: 2114

Alfa AF: 0.496 Hom.: 2726

Bravo AF: 0.471

Asia WGS AF: 0.695 AC: 2416 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.58
PhyloP100		-0.042
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: rs2227199; hg19: chr1-172359780;