7-45157859-C-T

Position:

• chr7-45157859-C-T

Variant summary

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

The NM_005856.3(RAMP3):​c.31C>T​(p.Leu11Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000475 in 1,264,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: RAMP3 NM_005856.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.579

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045677274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAMP3	NM_005856.3	c.31C>T	p.Leu11Phe	missense_variant	1/3	ENST00000242249.8	NP_005847.1
RAMP3	XM_006715631.4	c.31C>T	p.Leu11Phe	missense_variant	1/5		XP_006715694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAMP3	ENST00000242249.8	c.31C>T	p.Leu11Phe	missense_variant	1/3	1	NM_005856.3	ENSP00000242249.4
RAMP3	ENST00000496212.5	c.31C>T	p.Leu11Phe	missense_variant	1/4	4		ENSP00000418460.1
RAMP3	ENST00000481345.1	c.31C>T	p.Leu11Phe	missense_variant	1/4	4		ENSP00000419012.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000475 AC: 6 AN: 1264222 Hom.: 0 Cov.: 35 AF XY: 0.00000646 AC XY: 4 AN XY: 619528

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000596

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000487

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

The c.31C>T (p.L11F) alteration is located in exon 1 (coding exon 1) of the RAMP3 gene. This alteration results from a C to T substitution at nucleotide position 31, causing the leucine (L) at amino acid position 11 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.45	.;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.014
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.12
MutPred		0.21		Loss of disorder (P = 0.0625);Loss of disorder (P = 0.0625);Loss of disorder (P = 0.0625);
MVP		0.067
MPC		0.36
ClinPred		0.029	T
GERP RS		0.092
Varity_R		0.081
gMVP		0.63

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: rs1236184211; hg19: chr7-45197458;