7-45183335-G-A

Position:

chr7-45183335-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_005856.3(RAMP3):c.370G>A(p.Val124Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

RAMP3
NM_005856.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0370

Variant links:

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]

RAMP3 links:

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ACMG classification

Classification made for transcript

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=0.012921423).

BP6

Variant 7-45183335-G-A is Benign according to our data. Variant chr7-45183335-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2518274.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAMP3	NM_005856.3 linkuse as main transcript	c.370G>A	p.Val124Ile	missense_variant	3/3	ENST00000242249.8	NP_005847.1
RAMP3	XM_006715631.4 linkuse as main transcript	c.703G>A	p.Val235Ile	missense_variant	5/5		XP_006715694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RAMP3	ENST00000242249.8 linkuse as main transcript	c.370G>A	p.Val124Ile	missense_variant	3/3	1	NM_005856.3	ENSP00000242249	P2
RAMP3	ENST00000496212.5 linkuse as main transcript	c.370G>A	p.Val124Ile	missense_variant	3/4	4		ENSP00000418460	A2
RAMP3	ENST00000481345.1 linkuse as main transcript	c.370G>A	p.Val124Ile	missense_variant	3/4	4		ENSP00000419012	P2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251164

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000171

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

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

0.069

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.0

DANN

Benign

0.82

DEOGEN2

Benign

0.088

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.57

.;T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.12

N;N;N

REVEL

Benign

0.030

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.54

T;T;T

Polyphen

0.054

B;.;B

Vest4

0.048

MVP

0.28

MPC

0.29

ClinPred

0.020

GERP RS

-1.4

Varity_R

0.11

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over