12-32679339-A-G

Variant names:

• chr12-32679339-A-G
• rs191084732
• NM_001278464.2:c.-25A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_012062.5(DNM1L):​c.-25A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,569,678 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: DNM1L NM_012062.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.135
• Publications: 0 publications found

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]

DNM1L Gene-Disease associations (from GenCC):

• encephalopathy due to mitochondrial and peroxisomal fission defect

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• optic atrophy 5

  Inheritance: AD Classification: STRONG Submitted by: G2P
• encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant optic atrophy, classic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-32679339-A-G is Benign according to our data. Variant chr12-32679339-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 308384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00211 (321/152162) while in subpopulation AFR AF = 0.00698 (290/41538). AF 95% confidence interval is 0.00632. There are 1 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012062.5. 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
	DNM1L	NM_001278464.2	MANE Plus Clinical	c.-25A>G		5_prime_UTR	Exon 1 of 21	NP_001265393.1	O00429-6
	DNM1L	NM_012062.5	MANE Select	c.-25A>G		5_prime_UTR	Exon 1 of 20	NP_036192.2	O00429-1
	DNM1L	NM_001278465.2		c.-25A>G		5_prime_UTR	Exon 1 of 20	NP_001265394.1	O00429-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.-25A>G		5_prime_UTR	Exon 1 of 21	ENSP00000449089.1	O00429-6
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.-25A>G		5_prime_UTR	Exon 1 of 20	ENSP00000450399.1	O00429-1
	DNM1L	ENST00000381000.8	TSL:1	c.-25A>G		5_prime_UTR	Exon 1 of 20	ENSP00000370388.4	O00429-8

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152044 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00691

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000567 AC: 136 AN: 239940 AF XY: 0.000406

Gnomad AFR exome AF: 0.00744

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000466

Gnomad OTH exome AF: 0.000853

GnomAD4 exome AF: 0.000257 AC: 364 AN: 1417516 Hom.: 0 Cov.: 26 AF XY: 0.000213 AC XY: 151 AN XY: 707482

African (AFR) AF: 0.00614 AC: 200 AN: 32574

American (AMR) AF: 0.000386 AC: 17 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52304

Middle Eastern (MID) AF: 0.000885 AC: 5 AN: 5652

European-Non Finnish (NFE) AF: 0.000103 AC: 111 AN: 1074094

Other (OTH) AF: 0.000510 AC: 30 AN: 58860

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152162 Hom.: 1 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74404

African (AFR) AF: 0.00698 AC: 290 AN: 41538

American (AMR) AF: 0.00157 AC: 24 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67984

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00260

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		0.14
PromoterAI		0.062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	polymorphism

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: rs191084732; hg19: chr12-32832273;