rs193920935

Variant names:

• chr2-203457565-C-A
• rs193920935
• NM_213589.3:c.1123G>T

Variant summary

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

The NM_213589.3(RAPH1):​c.1123G>T​(p.Glu375*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAPH1 NM_213589.3 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.54
• Publications: 1 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]

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPH1	NM_213589.3	MANE Select	c.1123G>T	p.Glu375*	stop_gained	Exon 8 of 14	NP_998754.1	Q70E73-10
	RAPH1	NM_001439019.1		c.1279G>T	p.Glu427*	stop_gained	Exon 10 of 16	NP_001425948.1
	RAPH1	NM_001439027.1		c.1204G>T	p.Glu402*	stop_gained	Exon 9 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.1123G>T	p.Glu375*	stop_gained	Exon 8 of 14	ENSP00000316543.5	Q70E73-10
	RAPH1	ENST00000453034.5	TSL:1	c.1279G>T	p.Glu427*	stop_gained	Exon 10 of 15	ENSP00000406662.1	Q70E73-6
	RAPH1	ENST00000308091.8	TSL:1	c.1279G>T	p.Glu427*	stop_gained	Exon 10 of 16	ENSP00000311293.4	Q70E73-9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.5
Vest4		0.53
GERP RS		5.3
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs193920935; hg19: chr2-204322288; COSMIC: COSV57356103;