21-32298989-C-A

Position:

• chr21-32298989-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_001379228.1(MRAP):​c.18C>A​(p.Asn6Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,613,882 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: MRAP NM_001379228.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.745

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000335 (51/152238) while in subpopulation NFE AF= 0.0005 (34/68038). AF 95% confidence interval is 0.000367. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRAP	NM_001379228.1	c.18C>A	p.Asn6Lys	missense_variant	1/3	ENST00000303645.10	NP_001366157.1
MRAP	NM_178817.4	c.18C>A	p.Asn6Lys	missense_variant	3/5		NP_848932.1
MRAP	NM_206898.2	c.18C>A	p.Asn6Lys	missense_variant	3/5		NP_996781.1
MRAP	NM_001285394.2	c.-72+5857C>A		intron_variant			NP_001272323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRAP	ENST00000303645.10	c.18C>A	p.Asn6Lys	missense_variant	1/3	1	NM_001379228.1	ENSP00000306697	P1
MRAP	ENST00000399784.6	c.18C>A	p.Asn6Lys	missense_variant	3/5	1		ENSP00000382684	P1
MRAP	ENST00000339944.4	c.18C>A	p.Asn6Lys	missense_variant	1/3	1		ENSP00000343661
MRAP	ENST00000497833.1	n.177+5857C>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000354 AC: 89 AN: 251396 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135880

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000595 AC: 870 AN: 1461644 Hom.: 1 Cov.: 31 AF XY: 0.000584 AC XY: 425 AN XY: 727118

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000710

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74378

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000462 Hom.: 0

Bravo AF: 0.000389

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The c.18C>A (p.N6K) alteration is located in exon 3 (coding exon 1) of the MRAP gene. This alteration results from a C to A substitution at nucleotide position 18, causing the asparagine (N) at amino acid position 6 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.8
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.71	.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	-0.085	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.65
MutPred		0.18		Gain of ubiquitination at N6 (P = 0.0094);Gain of ubiquitination at N6 (P = 0.0094);Gain of ubiquitination at N6 (P = 0.0094);
MVP		0.77
MPC		0.44
ClinPred		0.16	T
GERP RS		-1.1
Varity_R		0.35
gMVP		0.55

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

Other links and lift over

dbSNP: rs138040820; hg19: chr21-33671300;