2-203440370-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_213589.3(RAPH1):​c.2820A>G​(p.Pro940Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,578,334 control chromosomes in the GnomAD database, including 236,589 homozygotes. 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 0.47 (17036 hom., cov: 25)
  • Exomes 𝑓: 0.55 (219553 hom.)
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPH1	NM_213589.3	c.2820A>G	p.Pro940Pro	synonymous_variant	Exon 14 of 14	ENST00000319170.10	NP_998754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPH1	ENST00000319170.10	c.2820A>G	p.Pro940Pro	synonymous_variant	Exon 14 of 14	1	NM_213589.3	ENSP00000316543.5

Frequencies

GnomAD3 genomes AF: 0.469 AC: 67371 AN: 143570 Hom.: 17052 Cov.: 25

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.520

GnomAD2 exomes AF: 0.514 AC: 124415 AN: 242010 AF XY: 0.530

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.454

Gnomad ASJ exome AF: 0.672

Gnomad EAS exome AF: 0.366

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.566

Gnomad OTH exome AF: 0.565

GnomAD4 exome AF: 0.549 AC: 787968 AN: 1434678 Hom.: 219553 Cov.: 36 AF XY: 0.553 AC XY: 393572 AN XY: 711584

African (AFR) AF: 0.210 AC: 6808 AN: 32466

American (AMR) AF: 0.456 AC: 19786 AN: 43356

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 17029 AN: 25256

East Asian (EAS) AF: 0.320 AC: 12266 AN: 38330

South Asian (SAS) AF: 0.630 AC: 53040 AN: 84164

European-Finnish (FIN) AF: 0.475 AC: 24170 AN: 50918

Middle Eastern (MID) AF: 0.641 AC: 3621 AN: 5650

European-Non Finnish (NFE) AF: 0.565 AC: 618590 AN: 1095516

Other (OTH) AF: 0.553 AC: 32658 AN: 59022

GnomAD4 genome AF: 0.469 AC: 67351 AN: 143656 Hom.: 17036 Cov.: 25 AF XY: 0.469 AC XY: 32748 AN XY: 69834

African (AFR) AF: 0.239 AC: 8874 AN: 37184

American (AMR) AF: 0.506 AC: 7334 AN: 14494

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2314 AN: 3414

East Asian (EAS) AF: 0.371 AC: 1747 AN: 4708

South Asian (SAS) AF: 0.630 AC: 2864 AN: 4544

European-Finnish (FIN) AF: 0.473 AC: 4527 AN: 9566

Middle Eastern (MID) AF: 0.707 AC: 205 AN: 290

European-Non Finnish (NFE) AF: 0.569 AC: 37875 AN: 66564

Other (OTH) AF: 0.515 AC: 1031 AN: 2002

Alfa AF: 0.406 Hom.: 6321

Bravo AF: 0.439

Asia WGS AF: 0.476 AC: 1657 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.3
DANN	Benign	0.56
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs3814365; hg19: chr2-204305093; COSMIC: COSV55584250; COSMIC: COSV55584250;