19-48720995-C-T

Variant names:

• chr19-48720995-C-T
• rs1446175729
• NM_017805.3:c.2695G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_017805.3(RASIP1):​c.2695G>A​(p.Asp899Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000692 in 1,444,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: RASIP1 NM_017805.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.96

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASIP1	NM_017805.3	c.2695G>A	p.Asp899Asn	missense_variant, splice_region_variant	Exon 12 of 12	ENST00000222145.9	NP_060275.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASIP1	ENST00000222145.9	c.2695G>A	p.Asp899Asn	missense_variant, splice_region_variant	Exon 12 of 12	1	NM_017805.3	ENSP00000222145.3
RASIP1	ENST00000601530.1	n.1189G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000692 AC: 10 AN: 1444182 Hom.: 0 Cov.: 31 AF XY: 0.00000419 AC XY: 3 AN XY: 716768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000906

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2695G>A (p.D899N) alteration is located in exon 12 (coding exon 11) of the RASIP1 gene. This alteration results from a G to A substitution at nucleotide position 2695, causing the aspartic acid (D) at amino acid position 899 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.21
Sift	Benign	0.086	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.23		Loss of loop (P = 0.1242);
MVP		0.65
MPC		0.61
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.32
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs1446175729; hg19: chr19-49224252;