rs80358231

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_001379228.1(MRAP):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000831 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

MRAP
NM_001379228.1 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.93

Variant links:

Genes affected

MRAP (HGNC:1304): (melanocortin 2 receptor accessory protein) This gene encodes a melanocortin receptor-interacting protein. The encoded protein regulates trafficking and function of the melanocortin 2 receptor in the adrenal gland. The encoded protein can also modulate signaling of other melanocortin receptors. Mutations in this gene have been associated with familial glucocorticoid deficiency type 2. Alternatively spliced transcript variants have been described. [provided by RefSeq, Dec 2009]

MRAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_001379228.1 (MRAP) was described as [Pathogenic] in ClinVar as 444067

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-32298974-G-A is Pathogenic according to our data. Variant chr21-32298974-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MRAP	NM_001379228.1 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/3	ENST00000303645.10
MRAP	NM_178817.4 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	3/5
MRAP	NM_206898.2 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	3/5
MRAP	NM_001285394.2 linkuse as main transcript	c.-72+5842G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRAP	ENST00000303645.10 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/3	1	NM_001379228.1	P1	Q8TCY5-4
MRAP	ENST00000399784.6 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	3/5	1		P1	Q8TCY5-4
MRAP	ENST00000339944.4 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/3	1			Q8TCY5-2
MRAP	ENST00000497833.1 linkuse as main transcript	n.177+5842G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251220

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000821

AC:

120

AN:

1461168

Hom.:

Cov.:

AF XY:

0.0000867

AC XY:

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid deficiency 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 28, 2014	The Met1? variant has been identified in 0.012% (1/8600) of European American chromosomes and 0.023% (1/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs80358231). The Met1? variant in MRAP has also been reported in at least 8 individuals with familial glucocorticoid deficiency (Metherell 2005). All these individuals were homozygous for the variant. This missense variant alters the evolutionary conserved initiating methionine and is predicted to lead to abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for familial glucocorticoid deficiency with recessive inheritance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -

Glucocorticoid deficiency 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Sep 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.30

T;T;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.74

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.14

MutationTaster

Benign

1.0

A;A;A;A

PROVEAN

Benign

-2.2

N;N;N

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.98

D;D;P

Vest4

0.93

MutPred

1.0

Loss of glycosylation at T5 (P = 0.1092);Loss of glycosylation at T5 (P = 0.1092);Loss of glycosylation at T5 (P = 0.1092);

MVP

0.95

ClinPred

0.97

GERP RS

4.2

Varity_R

0.92

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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