19-48721956-C-G

Variant names:

• chr19-48721956-C-G
• rs374430911
• NM_017805.3:c.2590G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_017805.3(RASIP1):​c.2590G>C​(p.Ala864Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000502 in 1,393,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A864S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: RASIP1 NM_017805.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70
• Publications: 2 publications found

Genes affected

RASIP1 (HGNC:24716): (Ras interacting protein 1) Enables GTPase binding activity and protein homodimerization activity. Involved in several processes, including negative regulation of Rho protein signal transduction; negative regulation of Rho-dependent protein serine/threonine kinase activity; and positive regulation of integrin activation. Located in cell-cell junction. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017805.3. 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
	RASIP1	NM_017805.3	MANE Select	c.2590G>C	p.Ala864Pro	missense	Exon 11 of 12	NP_060275.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASIP1	ENST00000222145.9	TSL:1 MANE Select	c.2590G>C	p.Ala864Pro	missense	Exon 11 of 12	ENSP00000222145.3	Q5U651
	RASIP1	ENST00000963671.1		c.2596G>C	p.Ala866Pro	missense	Exon 11 of 12	ENSP00000633730.1
	RASIP1	ENST00000862294.1		c.2590G>C	p.Ala864Pro	missense	Exon 11 of 12	ENSP00000532353.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000102 AC: 2 AN: 195674 AF XY: 0.00000944

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000792

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000502 AC: 7 AN: 1393312 Hom.: 0 Cov.: 30 AF XY: 0.00000435 AC XY: 3 AN XY: 689138

African (AFR) AF: 0.00 AC: 0 AN: 30370

American (AMR) AF: 0.000195 AC: 7 AN: 35834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22924

East Asian (EAS) AF: 0.00 AC: 0 AN: 36548

South Asian (SAS) AF: 0.00 AC: 0 AN: 78450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074542

Other (OTH) AF: 0.00 AC: 0 AN: 57296

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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	0.21
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.79		Gain of catalytic residue at P863 (P = 0.015)
MVP		0.44
MPC		1.8
ClinPred		0.94	D
GERP RS		3.5
Varity_R		0.72
gMVP		0.83
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs374430911; hg19: chr19-49225213;