rs2272238

chr12-32707368-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001278464.2(DNM1L):c.291G>A(p.Gly97=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,600,610 control chromosomes in the GnomAD database, including 16,194 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 0.15 (1899 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14295 hom.)
• Consequence: DNM1L NM_001278464.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001496
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.488

Genes affected

DNM1L (HGNC:2973): (dynamin 1 like) This gene encodes a member of the dynamin superfamily of GTPases. The encoded protein mediates mitochondrial and peroxisomal division, and is involved in developmentally regulated apoptosis and programmed necrosis. Dysfunction of this gene is implicated in several neurological disorders, including Alzheimer's disease. Mutations in this gene are associated with the autosomal dominant disorder, encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012442768).
• BP6: Variant 12-32707368-G-A is Benign according to our data. Variant chr12-32707368-G-A is described in ClinVar as [Benign]. Clinvar id is 260167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.488 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1L	NM_001278464.2	c.291G>A	p.Gly97=	splice_region_variant, synonymous_variant	4/21	ENST00000553257.6
DNM1L	NM_012062.5	c.252G>A	p.Gly84=	splice_region_variant, synonymous_variant	3/20	ENST00000549701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1L	ENST00000553257.6	c.291G>A	p.Gly97=	splice_region_variant, synonymous_variant	4/21	2	NM_001278464.2
DNM1L	ENST00000549701.6	c.252G>A	p.Gly84=	splice_region_variant, synonymous_variant	3/20	1	NM_012062.5

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23369 AN: 151682 Hom.: 1890 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0741

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.127 AC: 31378 AN: 246126 Hom.: 2179 AF XY: 0.130 AC XY: 17252 AN XY: 132954

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.0756

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.0974

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.137 AC: 198650 AN: 1448810 Hom.: 14295 Cov.: 29 AF XY: 0.138 AC XY: 99136 AN XY: 720482

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0839

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.0709

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.154 AC: 23394 AN: 151800 Hom.: 1899 Cov.: 32 AF XY: 0.152 AC XY: 11243 AN XY: 74120

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.0743

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.0904

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.170

Alfa AF: 0.149 Hom.: 3760

Bravo AF: 0.159

TwinsUK AF: 0.139 AC: 516

ALSPAC AF: 0.138 AC: 532

ESP6500AA AF: 0.196 AC: 861

ESP6500EA AF: 0.146 AC: 1251

ExAC AF: 0.133 AC: 16103

Asia WGS AF: 0.136 AC: 471 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Optic atrophy 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	8.2
Dann	Uncertain	0.98
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.22
ClinPred		0.031	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.076
SpliceAI score (max)		0.030		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: rs2272238; hg19: chr12-32860302; COSMIC: COSV56772870; COSMIC: COSV56772870;