21-32311867-C-G

Variant names:

• chr21-32311867-C-G
• rs17855143
• NM_001379228.1:c.390C>G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001379228.1(MRAP):​c.390C>G​(p.Thr130Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0075 in 1,614,154 control chromosomes in the GnomAD database, including 464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (430 hom.)
• Consequence: MRAP NM_001379228.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.280

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

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 21-32311867-C-G is Benign according to our data. Variant chr21-32311867-C-G is described in ClinVar as [Benign]. Clinvar id is 339683.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRAP	NM_001379228.1	c.390C>G	p.Thr130Thr	synonymous_variant	Exon 3 of 3	ENST00000303645.10	NP_001366157.1
URB1	NM_014825.3	c.*3051G>C		3_prime_UTR_variant	Exon 39 of 39	ENST00000382751.4	NP_055640.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRAP	ENST00000303645.10	c.390C>G	p.Thr130Thr	synonymous_variant	Exon 3 of 3	1	NM_001379228.1	ENSP00000306697.5
URB1	ENST00000382751	c.*3051G>C		3_prime_UTR_variant	Exon 39 of 39	1	NM_014825.3	ENSP00000372199.3

Frequencies

GnomAD3 genomes AF: 0.00727 AC: 1106 AN: 152224 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0880

Gnomad SAS AF: 0.0588

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0155 AC: 3863 AN: 249008 Hom.: 125 AF XY: 0.0172 AC XY: 2317 AN XY: 134888

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0842

Gnomad SAS exome AF: 0.0535

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00751 AC: 10984 AN: 1461812 Hom.: 430 Cov.: 31 AF XY: 0.00891 AC XY: 6483 AN XY: 727218

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.0521

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.000639

Gnomad4 OTH exome AF: 0.00873

GnomAD4 genome AF: 0.00737 AC: 1122 AN: 152342 Hom.: 34 Cov.: 32 AF XY: 0.00912 AC XY: 679 AN XY: 74490

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0880

Gnomad4 SAS AF: 0.0593

Gnomad4 FIN AF: 0.0200

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00179 Hom.: 1

Bravo AF: 0.00471

Asia WGS AF: 0.0900 AC: 313 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.1
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs17855143; hg19: chr21-33684178; COSMIC: COSV57936716; COSMIC: COSV57936716;