2-203439900-G-C

Variant names:

• chr2-203439900-G-C
• rs1559438510
• NM_213589.3:c.3290C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_213589.3(RAPH1):​c.3290C>G​(p.Thr1097Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAPH1 NM_213589.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.118523896).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPH1	NM_213589.3	MANE Select	c.3290C>G	p.Thr1097Ser	missense	Exon 14 of 14	NP_998754.1	Q70E73-10
	RAPH1	NM_001439019.1		c.3446C>G	p.Thr1149Ser	missense	Exon 16 of 16	NP_001425948.1
	RAPH1	NM_001439027.1		c.3371C>G	p.Thr1124Ser	missense	Exon 15 of 15	NP_001425956.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPH1	ENST00000319170.10	TSL:1 MANE Select	c.3290C>G	p.Thr1097Ser	missense	Exon 14 of 14	ENSP00000316543.5	Q70E73-10
	ABI2	ENST00000295851.10	TSL:1	c.*12548G>C		3_prime_UTR	Exon 11 of 11	ENSP00000295851.4	A0A7D9NKC8
	RAPH1	ENST00000374493.7	TSL:5	c.3446C>G	p.Thr1149Ser	missense	Exon 15 of 15	ENSP00000363617.3	C9K0J5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.070
Sift	Uncertain	0.016	D
Sift4G	Benign	0.47	T
Polyphen		0.0050	B
Vest4		0.15
MutPred		0.075		Gain of sheet (P = 0.1208)
MVP		0.23
MPC		0.20
ClinPred		0.60	D
GERP RS		4.7
Varity_R		0.081
gMVP		0.067
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1559438510; hg19: chr2-204304623;