NM_015569.5:c.2522+2215A>G

Variant names:

• chr1-172391024-A-G
• rs2227198
• NM_015569.5:c.2522+2215A>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+2215A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 152,104 control chromosomes in the GnomAD database, including 20,362 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 (20362 hom., cov: 32)
• Consequence: DNM3 NM_015569.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 9 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015569.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM3	NM_015569.5	MANE Select	c.2522+2215A>G		intron	N/A	NP_056384.2
	DNM3	NM_001350204.2		c.2540+2215A>G		intron	N/A	NP_001337133.1
	DNM3	NM_001136127.3		c.2510+2215A>G		intron	N/A	NP_001129599.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM3	ENST00000627582.3	TSL:1 MANE Select	c.2522+2215A>G		intron	N/A	ENSP00000486701.1
	DNM3	ENST00000367731.5	TSL:1	c.2510+2215A>G		intron	N/A	ENSP00000356705.1
	DNM3	ENST00000485254.3	TSL:1	c.2540+2215A>G		intron	N/A	ENSP00000429165.2

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72733 AN: 151986 Hom.: 20360 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.530

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

GnomAD4 genome AF: 0.478 AC: 72757 AN: 152104 Hom.: 20362 Cov.: 32 AF XY: 0.485 AC XY: 36053 AN XY: 74354

African (AFR) AF: 0.175 AC: 7283 AN: 41508

American (AMR) AF: 0.635 AC: 9698 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1919 AN: 3468

East Asian (EAS) AF: 0.871 AC: 4502 AN: 5168

South Asian (SAS) AF: 0.566 AC: 2726 AN: 4816

European-Finnish (FIN) AF: 0.547 AC: 5786 AN: 10572

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.573 AC: 38951 AN: 67986

Other (OTH) AF: 0.534 AC: 1128 AN: 2112

Alfa AF: 0.486 Hom.: 3076

Bravo AF: 0.474

Asia WGS AF: 0.696 AC: 2419 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.6
DANN	Benign	0.56
PhyloP100		0.0
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: rs2227198; hg19: chr1-172360164;