1-58530648-C-A

Variant names:

• chr1-58530648-C-A
• rs77980955
• NM_145243.5:c.1093G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP3 BP4_Moderate BP6_Very_Strong BS2

The NM_145243.5(OMA1):​c.1093G>T​(p.Asp365Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00361 in 872,802 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (11 hom.)
• Consequence: OMA1 NM_145243.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.61
• Publications: 15 publications found

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]

DAB1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 37

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.07886812).
• BP6: Variant 1-58530648-C-A is Benign according to our data. Variant chr1-58530648-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 713749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145243.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OMA1	NM_145243.5	MANE Select	c.1093G>T	p.Asp365Tyr	missense	Exon 6 of 9	NP_660286.1	Q96E52-1
	DAB1	NM_001379461.1		c.-729-3313G>T		intron	N/A	NP_001366390.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OMA1	ENST00000371226.8	TSL:1 MANE Select	c.1093G>T	p.Asp365Tyr	missense	Exon 6 of 9	ENSP00000360270.3	Q96E52-1
	OMA1	ENST00000906297.1		c.1093G>T	p.Asp365Tyr	missense	Exon 7 of 10	ENSP00000576356.1
	OMA1	ENST00000906298.1		c.1093G>T	p.Asp365Tyr	missense	Exon 6 of 9	ENSP00000576357.1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00536

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00333 AC: 837 AN: 251234 AF XY: 0.00345

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00365 AC: 2633 AN: 720470 Hom.: 11 Cov.: 0 AF XY: 0.00363 AC XY: 1398 AN XY: 384616

African (AFR) AF: 0.00106 AC: 21 AN: 19868

American (AMR) AF: 0.00189 AC: 83 AN: 43886

Ashkenazi Jewish (ASJ) AF: 0.00307 AC: 66 AN: 21490

East Asian (EAS) AF: 0.00 AC: 0 AN: 36486

South Asian (SAS) AF: 0.00215 AC: 154 AN: 71698

European-Finnish (FIN) AF: 0.00284 AC: 151 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4316

European-Non Finnish (NFE) AF: 0.00468 AC: 2028 AN: 433550

Other (OTH) AF: 0.00361 AC: 130 AN: 36024

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00307 AC XY: 229 AN XY: 74496

African (AFR) AF: 0.000962 AC: 40 AN: 41570

American (AMR) AF: 0.00333 AC: 51 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00535 AC: 364 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00410 Hom.: 4

Bravo AF: 0.00326

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00326 AC: 396

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00486

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.079	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.62
MPC		0.43
ClinPred		0.032	T
GERP RS		5.1
Varity_R		0.86
gMVP		0.88
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs77980955; hg19: chr1-58996320; COSMIC: COSV105265620; COSMIC: COSV105265620;