12-32679332-G-T

Position:

• chr12-32679332-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012062.5(DNM1L):​c.-32G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,484,520 control chromosomes in the GnomAD database, including 538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (265 hom., cov: 33)
  • Exomes 𝑓: 0.011 (273 hom.)
• Consequence: DNM1L NM_012062.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.581

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-32679332-G-T is Benign according to our data. Variant chr12-32679332-G-T is described in ClinVar as [Benign]. Clinvar id is 137129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1L	NM_001278464.2	c.-32G>T		5_prime_UTR_premature_start_codon_gain_variant	1/21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.-32G>T		5_prime_UTR_premature_start_codon_gain_variant	1/20	ENST00000549701.6	NP_036192.2
DNM1L	NM_001278464.2	c.-32G>T		5_prime_UTR_variant	1/21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.-32G>T		5_prime_UTR_variant	1/20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257	c.-32G>T		5_prime_UTR_premature_start_codon_gain_variant	1/21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701	c.-32G>T		5_prime_UTR_premature_start_codon_gain_variant	1/20	1	NM_012062.5	ENSP00000450399.1
DNM1L	ENST00000553257	c.-32G>T		5_prime_UTR_variant	1/21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701	c.-32G>T		5_prime_UTR_variant	1/20	1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5459 AN: 152242 Hom.: 263 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00791

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0132 AC: 3126 AN: 236356 Hom.: 104 AF XY: 0.0113 AC XY: 1455 AN XY: 128482

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.00307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00376

Gnomad FIN exome AF: 0.00105

Gnomad NFE exome AF: 0.00877

Gnomad OTH exome AF: 0.00690

GnomAD4 exome AF: 0.0109 AC: 14519 AN: 1332160 Hom.: 273 Cov.: 19 AF XY: 0.0105 AC XY: 7019 AN XY: 669320

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00407

Gnomad4 FIN exome AF: 0.000791

Gnomad4 NFE exome AF: 0.00942

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0359 AC: 5475 AN: 152360 Hom.: 265 Cov.: 33 AF XY: 0.0348 AC XY: 2591 AN XY: 74516

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00791

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.00803 Hom.: 7

Bravo AF: 0.0407

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

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	-0.73
CADD	Benign	7.3
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs114505859; hg19: chr12-32832266; COSMIC: COSV56774147; COSMIC: COSV56774147;