NM_213589.3:c.2820A>C

Variant names:

• chr2-203440370-T-G
• rs3814365
• NM_213589.3:c.2820A>C
• RAPH1 p.Pro940Pro

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_213589.3(RAPH1):​c.2820A>C​(p.Pro940Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,434,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAPH1 NM_213589.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.59
• Publications: 20 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.

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.2820A>C	p.Pro940Pro	synonymous	Exon 14 of 14	NP_998754.1	Q70E73-10
	RAPH1	NM_001439019.1		c.2976A>C	p.Pro992Pro	synonymous	Exon 16 of 16	NP_001425948.1
	RAPH1	NM_001439027.1		c.2901A>C	p.Pro967Pro	synonymous	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.2820A>C	p.Pro940Pro	synonymous	Exon 14 of 14	ENSP00000316543.5	Q70E73-10
	ABI2	ENST00000295851.10	TSL:1	c.*13018T>G		3_prime_UTR	Exon 11 of 11	ENSP00000295851.4	A0A7D9NKC8
	RAPH1	ENST00000374493.7	TSL:5	c.2976A>C	p.Pro992Pro	synonymous	Exon 15 of 15	ENSP00000363617.3	C9K0J5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 143666 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1434986 Hom.: 0 Cov.: 36 AF XY: 0.00000422 AC XY: 3 AN XY: 711744

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32468

American (AMR) AF: 0.00 AC: 0 AN: 43380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25274

East Asian (EAS) AF: 0.00 AC: 0 AN: 38334

South Asian (SAS) AF: 0.0000357 AC: 3 AN: 84150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1095768

Other (OTH) AF: 0.00 AC: 0 AN: 59036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 143750 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 69880

African (AFR) AF: 0.00 AC: 0 AN: 37202

American (AMR) AF: 0.00 AC: 0 AN: 14502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.00 AC: 0 AN: 4710

South Asian (SAS) AF: 0.00 AC: 0 AN: 4556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66598

Other (OTH) AF: 0.00 AC: 0 AN: 2002

Alfa AF: 0.00 Hom.: 6321

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.62
PhyloP100		-3.6
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3814365;

hg19: chr2-204305093;