rs2074654

Positions:

• chr7-45177416-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005856.3(RAMP3):​c.166T>C​(p.Trp56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,614,010 control chromosomes in the GnomAD database, including 3,379 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.057 (322 hom., cov: 33)
  • Exomes 𝑓: 0.061 (3057 hom.)
• Consequence: RAMP3 NM_005856.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

Genes affected

RAMP3 (HGNC:9845): (receptor activity modifying protein 3) The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, called receptor (calcitonin) activity modifying proteins (RAMPs). RAMPs are type I transmembrane proteins with an extracellular N terminus and a cytoplasmic C terminus. RAMPs are required to transport calcitonin-receptor-like receptor (CRLR) to the plasma membrane. CRLR, a receptor with seven transmembrane domains, can function as either a calcitonin-gene-related peptide (CGRP) receptor or an adrenomedullin receptor, depending on which members of the RAMP family are expressed. In the presence of this (RAMP3) protein, CRLR functions as an adrenomedullin receptor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043381453).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAMP3	NM_005856.3	c.166T>C	p.Trp56Arg	missense_variant	2/3	ENST00000242249.8	NP_005847.1
RAMP3	XM_006715631.4	c.499T>C	p.Trp167Arg	missense_variant	4/5		XP_006715694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAMP3	ENST00000242249.8	c.166T>C	p.Trp56Arg	missense_variant	2/3	1	NM_005856.3	ENSP00000242249.4
RAMP3	ENST00000496212.5	c.166T>C	p.Trp56Arg	missense_variant	2/4	4		ENSP00000418460.1
RAMP3	ENST00000481345.1	c.166T>C	p.Trp56Arg	missense_variant	2/4	4		ENSP00000419012.1

Frequencies

GnomAD3 genomes AF: 0.0567 AC: 8620 AN: 152076 Hom.: 320 Cov.: 33

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0602

Gnomad OTH AF: 0.0689

GnomAD3 exomes AF: 0.0662 AC: 16646 AN: 251430 Hom.: 668 AF XY: 0.0668 AC XY: 9082 AN XY: 135898

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.0843

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.0977

Gnomad SAS exome AF: 0.0736

Gnomad FIN exome AF: 0.0646

Gnomad NFE exome AF: 0.0615

Gnomad OTH exome AF: 0.0670

GnomAD4 exome AF: 0.0613 AC: 89607 AN: 1461816 Hom.: 3057 Cov.: 31 AF XY: 0.0618 AC XY: 44978 AN XY: 727224

Gnomad4 AFR exome AF: 0.0236

Gnomad4 AMR exome AF: 0.0832

Gnomad4 ASJ exome AF: 0.0463

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.0710

Gnomad4 FIN exome AF: 0.0641

Gnomad4 NFE exome AF: 0.0595

Gnomad4 OTH exome AF: 0.0595

GnomAD4 genome AF: 0.0567 AC: 8629 AN: 152194 Hom.: 322 Cov.: 33 AF XY: 0.0592 AC XY: 4401 AN XY: 74400

Gnomad4 AFR AF: 0.0262

Gnomad4 AMR AF: 0.0913

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.0763

Gnomad4 FIN AF: 0.0652

Gnomad4 NFE AF: 0.0602

Gnomad4 OTH AF: 0.0691

Alfa AF: 0.0624 Hom.: 821

Bravo AF: 0.0559

TwinsUK AF: 0.0556 AC: 206

ALSPAC AF: 0.0602 AC: 232

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.0598 AC: 514

ExAC AF: 0.0637 AC: 7739

Asia WGS AF: 0.0980 AC: 341 AN: 3478

EpiCase AF: 0.0709

EpiControl AF: 0.0696

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D;T;D
Eigen	Benign	0.042
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.51	.;T;T
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	3.0	M;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-13	D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.028	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.27
MutPred		0.33		Loss of ubiquitination at K55 (P = 0.0756);Loss of ubiquitination at K55 (P = 0.0756);Loss of ubiquitination at K55 (P = 0.0756);
MPC		0.81
ClinPred		0.13	T
GERP RS		1.8
Varity_R		0.68
gMVP		0.97

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: rs2074654; hg19: chr7-45217015; COSMIC: COSV54245097;