rs4916251

Variant names:

• chr1-172377256-T-A
• rs4916251
• NM_015569.5:c.1894-1762T>A

Variant summary

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

The NM_015569.5(DNM3):​c.1894-1762T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 151,482 control chromosomes in the GnomAD database, including 40,621 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 0.71 (40621 hom., cov: 29)
• Consequence: DNM3 NM_015569.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.855 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.1894-1762T>A		intron	N/A	NP_056384.2
	DNM3	NM_001350204.2		c.1912-1762T>A		intron	N/A	NP_001337133.1
	DNM3	NM_001136127.3		c.1882-1762T>A		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.1894-1762T>A		intron	N/A	ENSP00000486701.1
	DNM3	ENST00000367731.5	TSL:1	c.1882-1762T>A		intron	N/A	ENSP00000356705.1
	DNM3	ENST00000485254.3	TSL:1	c.1912-1762T>A		intron	N/A	ENSP00000429165.2

Frequencies

GnomAD3 genomes AF: 0.705 AC: 106754 AN: 151364 Hom.: 40592 Cov.: 29

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.877

Gnomad SAS AF: 0.787

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.777

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.744

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

GnomAD4 genome AF: 0.705 AC: 106820 AN: 151482 Hom.: 40621 Cov.: 29 AF XY: 0.708 AC XY: 52421 AN XY: 74012

African (AFR) AF: 0.392 AC: 16163 AN: 41238

American (AMR) AF: 0.809 AC: 12291 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.791 AC: 2740 AN: 3466

East Asian (EAS) AF: 0.876 AC: 4495 AN: 5130

South Asian (SAS) AF: 0.789 AC: 3790 AN: 4806

European-Finnish (FIN) AF: 0.802 AC: 8414 AN: 10494

Middle Eastern (MID) AF: 0.767 AC: 224 AN: 292

European-Non Finnish (NFE) AF: 0.831 AC: 56403 AN: 67850

Other (OTH) AF: 0.746 AC: 1569 AN: 2102

Alfa AF: 0.756 Hom.: 5673

Bravo AF: 0.693

Asia WGS AF: 0.818 AC: 2841 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.61
PhyloP100		-0.19
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: rs4916251; hg19: chr1-172346396;