Genetic Variant NM_005855.4:c.367A>C (chr2-237911703-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005855.4(RAMP1):c.367A>C(p.Ile123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I123V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

RAMP1
NM_005855.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.483

Publications

2 publications found

Variant links:

Genes affected

RAMP1 (HGNC:9843): (receptor activity modifying protein 1) 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 (RAMP1) protein, CRLR functions as a CGRP receptor. The RAMP1 protein is involved in the terminal glycosylation, maturation, and presentation of the CGRP receptor to the cell surface. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

RAMP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005855.4. 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
	RAMP1	NM_005855.4	MANE Select	c.367A>C	p.Ile123Leu	missense	Exon 3 of 3	NP_005846.1	O60894
	RAMP1	NM_001308353.2		c.301A>C	p.Ile101Leu	missense	Exon 4 of 4	NP_001295282.1	E9PC20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAMP1	ENST00000254661.5	TSL:1 MANE Select	c.367A>C	p.Ile123Leu	missense	Exon 3 of 3	ENSP00000254661.4	O60894
RAMP1	ENST00000884471.1		c.607A>C	p.Ile203Leu	missense	Exon 5 of 5	ENSP00000554530.1
RAMP1	ENST00000951440.1		c.364A>C	p.Ile122Leu	missense	Exon 3 of 3	ENSP00000621499.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250070

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.73

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.77

MutationAssessor

Pathogenic

3.0

PhyloP100

0.48

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

REVEL

Benign

0.26

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.015

Polyphen

0.74

Vest4

0.35

MutPred

0.66

Gain of catalytic residue at I123 (P = 0.0016)

MVP

0.51

MPC

0.024

ClinPred

0.71

GERP RS

-0.038

Varity_R

0.70

gMVP

0.76

Mutation Taster

=44/56

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over