chr1-58539090-G-A

Position:

• chr1-58539090-G-A

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.205C>T​(p.His69Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 872,884 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0076 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: OMA1 NM_145243.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.784

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=0.0035673082).
• BP6: Variant 1-58539090-G-A is Benign according to our data. Variant chr1-58539090-G-A is described in ClinVar as [Benign]. Clinvar id is 767673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00758 (1154/152260) while in subpopulation AFR AF= 0.0196 (815/41572). AF 95% confidence interval is 0.0185. There are 7 homozygotes in gnomad4. There are 555 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OMA1	NM_145243.5	c.205C>T	p.His69Tyr	missense_variant	2/9	ENST00000371226.8
DAB1	NM_001379461.1	c.-730+7613C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OMA1	ENST00000371226.8	c.205C>T	p.His69Tyr	missense_variant	2/9	1	NM_145243.5	P1

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1150 AN: 152142 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00354 AC: 889 AN: 251126 Hom.: 8 AF XY: 0.00307 AC XY: 417 AN XY: 135800

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00264 AC: 1904 AN: 720624 Hom.: 11 Cov.: 0 AF XY: 0.00243 AC XY: 935 AN XY: 384664

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.00624

Gnomad4 ASJ exome AF: 0.00763

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000823

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00611

GnomAD4 genome AF: 0.00758 AC: 1154 AN: 152260 Hom.: 7 Cov.: 33 AF XY: 0.00745 AC XY: 555 AN XY: 74448

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00998

Alfa AF: 0.00320 Hom.: 9

Bravo AF: 0.00944

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00348 AC: 422

Asia WGS AF: 0.00231 AC: 8 AN: 3478

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	Aug 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.0
DANN	Benign	0.39
DEOGEN2	Benign	0.0032	T;T;T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.57	T;T;T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.090	N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.28	N;N;N;N;N;.
REVEL	Benign	0.038
Sift	Benign	0.65	T;T;T;T;T;.
Sift4G	Benign	1.0	T;.;.;.;.;.
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.072
MVP		0.072
MPC		0.071
ClinPred		0.00055	T
GERP RS		0.47
Varity_R		0.014
gMVP		0.19

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: rs75220198; hg19: chr1-59004762; COSMIC: COSV62253756; COSMIC: COSV62253756;