rs184731250

chr12-32730998-C-T

Variant summary

Our verdict is Benign. Variant got -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 splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.25

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1L	NM_001278464.2	c.1119-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000553257.6
DNM1L	NM_012062.5	c.1080-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000549701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1L	ENST00000549701.6	c.1080-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_012062.5
DNM1L	ENST00000553257.6	c.1119-16C>T		splice_polypyrimidine_tract_variant, intron_variant		2	NM_001278464.2

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

GnomAD3 exomes AF: 0.00673 AC: 1691 AN: 251298 Hom.: 12 AF XY: 0.00686 AC XY: 932 AN XY: 135816

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 SAS exome AF: 0.00206

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

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00217

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00751

Gnomad4 OTH exome AF: 0.00707

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

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.00810

Gnomad4 OTH AF: 0.00807

Alfa AF: 0.00789 Hom.: 1

Bravo AF: 0.00559

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	12
Dann	Benign	0.85

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: rs184731250; hg19: chr12-32883932;