rs371512174

Variant names:

• chr1-172407798-G-A
• rs371512174
• NM_015569.5:c.2549G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-172407798-G-A
• chr1-172407798-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_015569.5(DNM3):​c.2549G>A​(p.Arg850His) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,612,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DNM3 NM_015569.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26
• 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC102724528 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.272142).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM3	NM_015569.5	MANE Select	c.2549G>A	p.Arg850His	missense	Exon 21 of 21	NP_056384.2
	DNM3	NM_001350204.2		c.2567G>A	p.Arg856His	missense	Exon 21 of 21	NP_001337133.1	Q9UQ16-1
	DNM3	NM_001136127.3		c.2537G>A	p.Arg846His	missense	Exon 20 of 20	NP_001129599.1	Q9UQ16-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM3	ENST00000627582.3	TSL:1 MANE Select	c.2549G>A	p.Arg850His	missense	Exon 21 of 21	ENSP00000486701.1	Q9UQ16-3
	DNM3	ENST00000367731.5	TSL:1	c.2537G>A	p.Arg846His	missense	Exon 20 of 20	ENSP00000356705.1	Q9UQ16-2
	DNM3	ENST00000485254.3	TSL:1	c.2541-10483G>A		intron	N/A	ENSP00000429165.2	H0YBC6

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151836 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000522 AC: 13 AN: 249224 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1461130 Hom.: 0 Cov.: 30 AF XY: 0.0000991 AC XY: 72 AN XY: 726854

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.0000895 AC: 4 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000131 AC: 146 AN: 1111420

Other (OTH) AF: 0.0000166 AC: 1 AN: 60338

GnomAD4 genome AF: 0.0000790 AC: 12 AN: 151836 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74176

African (AFR) AF: 0.0000242 AC: 1 AN: 41334

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67914

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.48
MVP		0.73
ClinPred		0.26	T
GERP RS		5.8
Varity_R		0.19
gMVP		0.12
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs371512174; hg19: chr1-172376938; COSMIC: COSV62455165;