12-32744154-A-T

Variant names:

• chr12-32744154-A-T
• rs1971911
• NM_001278464.2:c.*744A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278464.2(DNM1L):​c.*744A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,196 control chromosomes in the GnomAD database, including 1,904 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1904 hom., cov: 32)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: DNM1L NM_001278464.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.727
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-32744154-A-T is Benign according to our data. Variant chr12-32744154-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 308409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 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.*744A>T		3_prime_UTR	Exon 21 of 21	NP_001265393.1
	DNM1L	NM_012062.5	MANE Select	c.*744A>T		3_prime_UTR	Exon 20 of 20	NP_036192.2
	DNM1L	NM_001278465.2		c.*744A>T		3_prime_UTR	Exon 20 of 20	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.*744A>T		3_prime_UTR	Exon 21 of 21	ENSP00000449089.1
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.*744A>T		3_prime_UTR	Exon 20 of 20	ENSP00000450399.1
	DNM1L	ENST00000381000.8	TSL:1	c.*744A>T		3_prime_UTR	Exon 20 of 20	ENSP00000370388.4

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23358 AN: 152060 Hom.: 1898 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0895

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.165

GnomAD4 exome AF: 0.0556 AC: 1 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0625 AC: 1 AN: 16

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.154 AC: 23377 AN: 152178 Hom.: 1904 Cov.: 32 AF XY: 0.151 AC XY: 11246 AN XY: 74414

African (AFR) AF: 0.204 AC: 8469 AN: 41496

American (AMR) AF: 0.128 AC: 1965 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3464

East Asian (EAS) AF: 0.0743 AC: 385 AN: 5180

South Asian (SAS) AF: 0.124 AC: 597 AN: 4828

European-Finnish (FIN) AF: 0.0895 AC: 948 AN: 10596

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9770 AN: 68002

Other (OTH) AF: 0.167 AC: 352 AN: 2114

Alfa AF: 0.0762 Hom.: 92

Bravo AF: 0.159

Asia WGS AF: 0.133 AC: 460 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary Sideroblastic Anemia with Myopathy and Lactic Acidosis (1)
-	-	1	Myopathy, lactic acidosis, and sideroblastic anemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.5
DANN	Benign	0.75
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs1971911; hg19: chr12-32897088;