rs184731250

Variant names:

• chr12-32730998-C-T
• rs184731250
• NM_001278464.2:c.1119-16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278464.2(DNM1L):​c.1119-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.007 in 1,613,590 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (50 hom.)
• Consequence: DNM1L NM_001278464.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.25
• 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]

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=-0.52).
• BP6: Variant 12-32730998-C-T is Benign according to our data. Variant chr12-32730998-C-T is described in ClinVar as Benign. ClinVar VariationId is 260164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00642 (978/152246) while in subpopulation AMR AF = 0.0109 (166/15290). AF 95% confidence interval is 0.00951. There are 8 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

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.1119-16C>T		intron	N/A	NP_001265393.1
	DNM1L	NM_012062.5	MANE Select	c.1080-16C>T		intron	N/A	NP_036192.2
	DNM1L	NM_001278465.2		c.1119-16C>T		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.1119-16C>T		intron	N/A	ENSP00000449089.1
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.1080-16C>T		intron	N/A	ENSP00000450399.1
	DNM1L	ENST00000381000.8	TSL:1	c.1119-16C>T		intron	N/A	ENSP00000370388.4

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 979 AN: 152130 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00810

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00673 AC: 1691 AN: 251298 AF XY: 0.00686

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00593

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.00839

Gnomad OTH exome AF: 0.00979

GnomAD4 exome AF: 0.00706 AC: 10317 AN: 1461344 Hom.: 50 Cov.: 32 AF XY: 0.00691 AC XY: 5026 AN XY: 726976

African (AFR) AF: 0.00134 AC: 45 AN: 33464

American (AMR) AF: 0.00602 AC: 269 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 379 AN: 26122

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39618

South Asian (SAS) AF: 0.00217 AC: 187 AN: 86232

European-Finnish (FIN) AF: 0.0117 AC: 625 AN: 53336

Middle Eastern (MID) AF: 0.00660 AC: 38 AN: 5756

European-Non Finnish (NFE) AF: 0.00751 AC: 8345 AN: 1111732

Other (OTH) AF: 0.00707 AC: 427 AN: 60364

GnomAD4 genome AF: 0.00642 AC: 978 AN: 152246 Hom.: 8 Cov.: 32 AF XY: 0.00673 AC XY: 501 AN XY: 74438

African (AFR) AF: 0.00164 AC: 68 AN: 41548

American (AMR) AF: 0.0109 AC: 166 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00810 AC: 551 AN: 68020

Other (OTH) AF: 0.00807 AC: 17 AN: 2106

Alfa AF: 0.00789 Hom.: 1

Bravo AF: 0.00559

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs184731250; hg19: chr12-32883932;