21-32299077-CG-C

Variant names:

• chr21-32299077-CG-C
• rs1476574441
• NM_001379228.1:c.106+1delG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001379228.1(MRAP):​c.106+1delG variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000806 in 1,613,104 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MRAP NM_001379228.1 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.48

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of 22, new splice context is: ccgGTcaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-32299077-CG-C is Pathogenic according to our data. Variant chr21-32299077-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 444068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-32299077-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRAP	NM_001379228.1	c.106+1delG		splice_donor_variant, intron_variant	Intron 1 of 2	ENST00000303645.10	NP_001366157.1
MRAP	NM_178817.4	c.106+1delG		splice_donor_variant, intron_variant	Intron 3 of 4		NP_848932.1
MRAP	NM_001285394.2	c.-72+5946delG		intron_variant	Intron 2 of 3		NP_001272323.1
MRAP	NM_206898.2	c.106+1delG		splice_donor_variant, intron_variant	Intron 3 of 4		NP_996781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRAP	ENST00000303645.10	c.106+1delG		splice_donor_variant, intron_variant	Intron 1 of 2	1	NM_001379228.1	ENSP00000306697.5
MRAP	ENST00000399784.6	c.106+1delG		splice_donor_variant, intron_variant	Intron 3 of 4	1		ENSP00000382684.2
MRAP	ENST00000339944.4	c.106+1delG		splice_donor_variant, intron_variant	Intron 1 of 2	1		ENSP00000343661.4
MRAP	ENST00000497833.1	n.177+5946delG		intron_variant	Intron 2 of 3	1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250868 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135634

Gnomad AFR exome AF: 0.0000619

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460858 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726758

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucocorticoid deficiency 2 Pathogenic:2

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with MRAP related disorder (ClinVar ID: VCV000444068 / PMID: 15654338). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Glucocorticoid deficiency 1 Pathogenic:1

Oct 04, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1476574441; hg19: chr21-33671388;