1-172379182-C-T

Position:

• chr1-172379182-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015569.5(DNM3):​c.2058C>T​(p.Asn686Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,599,870 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (23 hom.)
• Consequence: DNM3 NM_015569.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0007614
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.297

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-172379182-C-T is Benign according to our data. Variant chr1-172379182-C-T is described in ClinVar as [Benign]. Clinvar id is 791227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.297 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00876 (1332/152104) while in subpopulation AFR AF= 0.0296 (1230/41536). AF 95% confidence interval is 0.0282. There are 15 homozygotes in gnomad4. There are 605 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM3	NM_015569.5	c.2058C>T	p.Asn686Asn	splice_region_variant, synonymous_variant	18/21	ENST00000627582.3	NP_056384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM3	ENST00000627582.3	c.2058C>T	p.Asn686Asn	splice_region_variant, synonymous_variant	18/21	1	NM_015569.5	ENSP00000486701.1

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1323 AN: 151986 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00427

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00240 AC: 558 AN: 232490 Hom.: 8 AF XY: 0.00197 AC XY: 247 AN XY: 125694

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.000879

GnomAD4 exome AF: 0.000977 AC: 1415 AN: 1447766 Hom.: 23 Cov.: 30 AF XY: 0.000844 AC XY: 607 AN XY: 718950

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00187

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000357

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00876 AC: 1332 AN: 152104 Hom.: 15 Cov.: 32 AF XY: 0.00814 AC XY: 605 AN XY: 74364

Gnomad4 AFR AF: 0.0296

Gnomad4 AMR AF: 0.00426

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00267 Hom.: 6

Bravo AF: 0.0101

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00076
dbscSNV1_RF	Benign	0.30
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

LitVar

Other links and lift over

dbSNP: rs139523475; hg19: chr1-172348322;