1-58534181-T-C

Position:

• chr1-58534181-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145243.5(OMA1):​c.880A>G​(p.Ile294Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 871,604 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (13 hom.)
• Consequence: OMA1 NM_145243.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.781

Genes affected

OMA1 (HGNC:29661): (OMA1 zinc metallopeptidase) Enables metalloendopeptidase activity. Involved in several processes, including HRI-mediated signaling; proteolysis; and regulation of mitochondrion organization. Located in mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

DAB1 (HGNC:2661): (DAB adaptor protein 1) The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. In mice, the disabled-1 gene plays a central role in brain development, directing the migration of cortical neurons past previously formed neurons to reach their proper layer. This gene is similar to disabled-1, and the protein encoded by this gene is thought to be a signal transducer that interacts with protein kinase pathways to regulate neuronal positioning in the developing brain. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023922026).
• BP6: Variant 1-58534181-T-C is Benign according to our data. Variant chr1-58534181-T-C is described in ClinVar as [Benign]. Clinvar id is 773636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00173 (263/152348) while in subpopulation EAS AF= 0.0291 (151/5188). AF 95% confidence interval is 0.0253. There are 5 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OMA1	NM_145243.5	c.880A>G	p.Ile294Val	missense_variant	4/9	ENST00000371226.8
DAB1	NM_001379461.1	c.-729-6846A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OMA1	ENST00000371226.8	c.880A>G	p.Ile294Val	missense_variant	4/9	1	NM_145243.5	P1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152230 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00300 AC: 750 AN: 249724 Hom.: 5 AF XY: 0.00298 AC XY: 402 AN XY: 134878

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.0280

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00199 AC: 1432 AN: 719256 Hom.: 13 Cov.: 0 AF XY: 0.00200 AC XY: 768 AN XY: 383852

Gnomad4 AFR exome AF: 0.000101

Gnomad4 AMR exome AF: 0.0000918

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.0187

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.00173

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.00173 AC: 263 AN: 152348 Hom.: 5 Cov.: 33 AF XY: 0.00205 AC XY: 153 AN XY: 74498

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.0291

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00169 Hom.: 1

Bravo AF: 0.00162

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00250 AC: 303

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.7
DANN	Benign	0.70
DEOGEN2	Benign	0.027	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.19	N;N
REVEL	Benign	0.061
Sift	Benign	0.28	T;T
Sift4G	Benign	0.28	T;.
Polyphen		0.0	B;.
Vest4		0.091
MVP		0.18
MPC		0.054
ClinPred		0.0024	T
GERP RS		2.7
Varity_R		0.022
gMVP		0.11

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: rs75129043; hg19: chr1-58999853;