chr21-32311866-C-T

Variant names:

• chr21-32311866-C-T
• rs114530014
• NM_001379228.1:c.389C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.68
• Publications: 2 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379228.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRAP	NM_001379228.1	MANE Select	c.389C>T	p.Thr130Ile	missense	Exon 3 of 3	NP_001366157.1	Q8TCY5-4
	URB1	NM_014825.3	MANE Select	c.*3052G>A		3_prime_UTR	Exon 39 of 39	NP_055640.2
	MRAP	NM_178817.4		c.389C>T	p.Thr130Ile	missense	Exon 5 of 5	NP_848932.1	Q8TCY5-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRAP	ENST00000303645.10	TSL:1 MANE Select	c.389C>T	p.Thr130Ile	missense	Exon 3 of 3	ENSP00000306697.5	Q8TCY5-4
	MRAP	ENST00000399784.6	TSL:1	c.389C>T	p.Thr130Ile	missense	Exon 5 of 5	ENSP00000382684.2	Q8TCY5-4
	URB1	ENST00000382751.4	TSL:1 MANE Select	c.*3052G>A		3_prime_UTR	Exon 39 of 39	ENSP00000372199.3	O60287

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2140 AN: 152230 Hom.: 47 Cov.: 32

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

GnomAD2 exomes AF: 0.00353 AC: 880 AN: 248994 AF XY: 0.00254

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 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.: 34 Cov.: 31 AF XY: 0.00109 AC XY: 793 AN XY: 727212

African (AFR) AF: 0.0444 AC: 1487 AN: 33480

American (AMR) AF: 0.00250 AC: 112 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000612 AC: 68 AN: 1112010

Other (OTH) AF: 0.00308 AC: 186 AN: 60392

GnomAD4 genome AF: 0.0141 AC: 2141 AN: 152348 Hom.: 46 Cov.: 32 AF XY: 0.0131 AC XY: 978 AN XY: 74496

African (AFR) AF: 0.0488 AC: 2031 AN: 41586

American (AMR) AF: 0.00483 AC: 74 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68028

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00495 Hom.: 29

Bravo AF: 0.0155

ESP6500AA AF: 0.0497 AC: 219

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00457 AC: 555

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glucocorticoid deficiency 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.034	D
Polyphen		0.81	P
Vest4		0.10
MVP		0.84
MPC		0.13
ClinPred		0.016	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.038
gMVP		0.073
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs114530014; hg19: chr21-33684177;