Genetic Variant METAP1:p.Ala378Ala (chr4-99061290-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015143.3(METAP1):c.1134A>G(p.Ala378Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,796 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 16 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 16 hom. )

Consequence

METAP1
NM_015143.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.629

Variant links:

Genes affected

METAP1 (HGNC:15789): (methionyl aminopeptidase 1) Predicted to enable aminopeptidase activity and metalloexopeptidase activity. Involved in platelet aggregation. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

METAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 4-99061290-A-G is Benign according to our data. Variant chr4-99061290-A-G is described in ClinVar as [Benign]. Clinvar id is 783426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.629 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00732 (1115/152332) while in subpopulation AFR AF= 0.0258 (1074/41580). AF 95% confidence interval is 0.0245. There are 16 homozygotes in gnomad4. There are 529 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METAP1	NM_015143.3 link	c.1134A>G	p.Ala378Ala	synonymous_variant	Exon 11 of 11	ENST00000296411.11	NP_055958.2	P53582

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
METAP1	ENST00000296411.11 link	c.1134A>G	p.Ala378Ala	synonymous_variant	Exon 11 of 11	1	NM_015143.3	ENSP00000296411.6	P53582
METAP1	ENST00000514051.1 link	c.324A>G	p.Ala108Ala	synonymous_variant	Exon 3 of 3	1		ENSP00000422689.1	H0Y903
METAP1	ENST00000510133.5 link	c.486A>G	p.Ala162Ala	synonymous_variant	Exon 4 of 4	5		ENSP00000423071.1	H0Y955

Frequencies

GnomAD3 genomes

AF:

0.00723

AC:

1101

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00187

AC:

466

AN:

248720

Hom.:

AF XY:

0.00136

AC XY:

184

AN XY:

134948

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.000996

GnomAD4 exome

AF:

0.000831

AC:

1214

AN:

1461464

Hom.:

Cov.:

AF XY:

0.000710

AC XY:

516

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.0261

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.00207

GnomAD4 genome

AF:

0.00732

AC:

1115

AN:

152332

Hom.:

Cov.:

AF XY:

0.00710

AC XY:

529

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0258

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00829

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.89

DANN

Benign

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over