1-178299992-A-C

Variant names:

• chr1-178299992-A-C
• rs765908750
• NM_170692.4:c.331A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170692.4(RASAL2):​c.331A>C​(p.Ile111Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASAL2 NM_170692.4 missense, splice_region
• Scores: Splicing: ADA: 0.0003155
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 0 publications found

Genes affected

RASAL2 (HGNC:9874): (RAS protein activator like 2) This gene encodes a protein that contains the GAP-related domain (GRD), a characteristic domain of GTPase-activating proteins (GAPs). GAPs function as activators of Ras superfamily of small GTPases. The protein encoded by this gene is able to complement the defective RasGAP function in a yeast system. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08251837).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170692.4. 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
	RASAL2	NM_170692.4	MANE Select	c.331A>C	p.Ile111Leu	missense splice_region	Exon 3 of 18	NP_733793.2	Q9UJF2-2
	RASAL2	NM_001437625.1		c.331A>C	p.Ile111Leu	missense splice_region	Exon 3 of 19	NP_001424554.1
	RASAL2	NM_001437626.1		c.331A>C	p.Ile111Leu	missense splice_region	Exon 3 of 18	NP_001424555.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASAL2	ENST00000367649.8	TSL:1 MANE Select	c.331A>C	p.Ile111Leu	missense splice_region	Exon 3 of 18	ENSP00000356621.3	Q9UJF2-2
	RASAL2	ENST00000696605.1		c.718A>C	p.Ile240Leu	missense splice_region	Exon 3 of 18	ENSP00000512749.1	A0A8Q3SIU1
	RASAL2	ENST00000902905.1		c.331A>C	p.Ile111Leu	missense splice_region	Exon 3 of 18	ENSP00000572964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.66
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.040
Sift	Benign	0.33	T
Sift4G	Benign	0.58	T
Vest4		0.24
MutPred		0.18		Loss of methylation at K109 (P = 0.0658)
MVP		0.088
MPC		0.22
ClinPred		0.23	T
GERP RS		-1.4
gMVP		0.097
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.090		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: rs765908750; hg19: chr1-178269127;