21-32311866-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379228.1(MRAP):c.389C>T(p.Thr130Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,614,154 control chromosomes in the GnomAD database, including 80 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T130T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.014 ( 46 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 34 hom. )

Consequence

MRAP
NM_001379228.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.68

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:

URB1 (HGNC:17344): (URB1 ribosome biogenesis homolog) Enables RNA binding activity. Predicted to be involved in maturation of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) and maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Located in fibrillar center. [provided by Alliance of Genome Resources, Apr 2022]

URB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002300024).

BP6

Variant 21-32311866-C-T is Benign according to our data. Variant chr21-32311866-C-T is described in ClinVar as [Benign]. Clinvar id is 339682.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 = 0.0141 (2141/152348) while in subpopulation AFR AF= 0.0488 (2031/41586). AF 95% confidence interval is 0.0471. There are 46 homozygotes in gnomad4. There are 978 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRAP	NM_001379228.1 link	c.389C>T	p.Thr130Ile	missense_variant	Exon 3 of 3	ENST00000303645.10	NP_001366157.1
URB1	NM_014825.3 link	c.*3052G>A		3_prime_UTR_variant	Exon 39 of 39	ENST00000382751.4	NP_055640.2	O60287

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRAP	ENST00000303645.10 link	c.389C>T	p.Thr130Ile	missense_variant	Exon 3 of 3	1	NM_001379228.1	ENSP00000306697.5		Q8TCY5-4
URB1	ENST00000382751 link	c.*3052G>A		3_prime_UTR_variant	Exon 39 of 39	1	NM_014825.3	ENSP00000372199.3		O60287

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2140

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00353

AC:

880

AN:

248994

Hom.:

AF XY:

0.00254

AC XY:

342

AN XY:

134894

show subpopulations

Gnomad AFR exome

AF:

0.0478

Gnomad AMR exome

AF:

0.00243

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:

0.0000808

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00128

AC:

1867

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

793

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0444

Gnomad4 AMR exome

AF:

0.00250

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000612

Gnomad4 OTH exome

AF:

0.00308

GnomAD4 genome

AF:

0.0141

AC:

2141

AN:

152348

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

978

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0488

Gnomad4 AMR

AF:

0.00483

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.00230

Hom.:

Bravo

AF:

0.0155

ESP6500AA

AF:

0.0497

AC:

219

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00457

AC:

555

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glucocorticoid deficiency 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.41

.;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.34

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.76

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.034

D;D

Polyphen

0.81

P;P

Vest4

0.10

MVP

0.84

MPC

0.13

ClinPred

0.016

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.038

gMVP

0.073

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