21-32311804-C-A

Variant names:

• chr21-32311804-C-A
• NM_001379228.1:c.327C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001379228.1(MRAP):​c.327C>A​(p.Ser109Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRAP NM_001379228.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.191

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043615222).
• BP6: Variant 21-32311804-C-A is Benign according to our data. Variant chr21-32311804-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3203845.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRAP	NM_001379228.1	c.327C>A	p.Ser109Arg	missense_variant	Exon 3 of 3	ENST00000303645.10	NP_001366157.1
URB1	NM_014825.3	c.*3114G>T		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.327C>A	p.Ser109Arg	missense_variant	Exon 3 of 3	1	NM_001379228.1	ENSP00000306697.5
URB1	ENST00000382751	c.*3114G>T		3_prime_UTR_variant	Exon 39 of 39	1	NM_014825.3	ENSP00000372199.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 20, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.3
DANN	Benign	0.64
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.32	.;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.77	N;N
REVEL	Benign	0.19
Sift	Benign	0.95	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0010	B;B
Vest4		0.087
MutPred		0.20		Loss of phosphorylation at S109 (P = 0.0241);Loss of phosphorylation at S109 (P = 0.0241);
MVP		0.45
MPC		0.077
ClinPred		0.058	T
GERP RS		1.0
Varity_R		0.023
gMVP		0.042

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-33684115;