Genetic Variant RAPH1:p.Pro1086Leu (chr2-203439933-G-A) – 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_213589.3(RAPH1):c.3257C>T(p.Pro1086Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P1086R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

RAPH1
NM_213589.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.65

Publications

0 publications found

Variant links:

Genes affected

RAPH1 (HGNC:14436): (Ras association (RalGDS/AF-6) and pleckstrin homology domains 1) This gene encodes a protein that belongs to the Mig10/Rap1-interacting adaptor molecule/Lamellipodin family of adapter proteins, which function in cell migration. Members of this family contain pleckstrin-homology domains, Ras-association domains, and proline-rich C-termini. The protein encoded by this gene regulates actin dynamics through interaction with Ena/Vasodilator proteins as well as direct binding to filamentous actin to regulate actin network assembly. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

RAPH1 links:

ABI2 (HGNC:24011): (abl interactor 2) Enables several functions, including SH3 domain binding activity; identical protein binding activity; and ubiquitin protein ligase binding activity. Contributes to small GTPase binding activity. Involved in Rac protein signal transduction; positive regulation of cellular component organization; and zonula adherens assembly. Acts upstream of or within peptidyl-tyrosine phosphorylation. Located in several cellular components, including filopodium tip; lamellipodium; and nucleoplasm. Part of SCAR complex. Is active in adherens junction. Colocalizes with actin filament. [provided by Alliance of Genome Resources, Apr 2022]

ABI2 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_213589.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAPH1	NM_213589.3	MANE Select	c.3257C>T	p.Pro1086Leu	missense	Exon 14 of 14	NP_998754.1	Q70E73-10
RAPH1	NM_001439019.1		c.3413C>T	p.Pro1138Leu	missense	Exon 16 of 16	NP_001425948.1
RAPH1	NM_001439027.1		c.3338C>T	p.Pro1113Leu	missense	Exon 15 of 15	NP_001425956.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAPH1	ENST00000319170.10	TSL:1 MANE Select	c.3257C>T	p.Pro1086Leu	missense	Exon 14 of 14	ENSP00000316543.5	Q70E73-10
ABI2	ENST00000295851.10	TSL:1	c.*12581G>A		3_prime_UTR	Exon 11 of 11	ENSP00000295851.4	A0A7D9NKC8
RAPH1	ENST00000374493.7	TSL:5	c.3413C>T	p.Pro1138Leu	missense	Exon 15 of 15	ENSP00000363617.3	C9K0J5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.017

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.66

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.4

PhyloP100

9.6

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.049

Vest4

0.65

MutPred

0.31

Gain of sheet (P = 0.0149)

MVP

0.69

MPC

0.23

ClinPred

0.99

GERP RS

3.8

Varity_R

0.21

gMVP

0.26

Mutation Taster

=60/40

polymorphism

(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