chr12-32740389-TC-T

Variant names:

• chr12-32740389-TC-T
• rs863223951
• NM_001278464.2:c.1924-15delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001278464.2(DNM1L):​c.1924-15delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,611,928 control chromosomes in the GnomAD database, including 165 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (88 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (77 hom.)
• Consequence: DNM1L NM_001278464.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0770
• Publications: 1 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]

YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

YARS2 Gene-Disease associations (from GenCC):

• myopathy, lactic acidosis, and sideroblastic anemia 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• myopathy, lactic acidosis, and sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP6: Variant 12-32740389-TC-T is Benign according to our data. Variant chr12-32740389-TC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 214306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278464.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	NM_001278464.2	MANE Plus Clinical	c.1924-15delC		intron	N/A	NP_001265393.1
	DNM1L	NM_012062.5	MANE Select	c.1885-15delC		intron	N/A	NP_036192.2
	DNM1L	NM_001278465.2		c.1891-15delC		intron	N/A	NP_001265394.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.1924-15delC		intron	N/A	ENSP00000449089.1
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.1885-15delC		intron	N/A	ENSP00000450399.1
	DNM1L	ENST00000381000.8	TSL:1	c.1891-15delC		intron	N/A	ENSP00000370388.4

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2777 AN: 152118 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00488 AC: 1216 AN: 249420 AF XY: 0.00354

Gnomad AFR exome AF: 0.0682

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.00180 AC: 2621 AN: 1459692 Hom.: 77 Cov.: 30 AF XY: 0.00155 AC XY: 1127 AN XY: 725994

African (AFR) AF: 0.0648 AC: 2166 AN: 33422

American (AMR) AF: 0.00298 AC: 133 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5764

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1110420

Other (OTH) AF: 0.00345 AC: 208 AN: 60298

GnomAD4 genome AF: 0.0183 AC: 2788 AN: 152236 Hom.: 88 Cov.: 32 AF XY: 0.0174 AC XY: 1298 AN XY: 74432

African (AFR) AF: 0.0642 AC: 2668 AN: 41530

American (AMR) AF: 0.00523 AC: 80 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68020

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00952 Hom.: 6

Bravo AF: 0.0206

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in MITONUC-MITOP panel(s).

Optic atrophy 5;C3280660:Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Benign:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.077
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs863223951; hg19: chr12-32893323;