1-178300106-G-A

Variant names:

• chr1-178300106-G-A
• rs1038193873
• NM_170692.4:c.445G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_170692.4(RASAL2):​c.445G>A​(p.Ala149Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RASAL2 NM_170692.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.552

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.074165285).
• BP6: Variant 1-178300106-G-A is Benign according to our data. Variant chr1-178300106-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2543685.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL2	NM_170692.4	c.445G>A	p.Ala149Thr	missense_variant	Exon 3 of 18	ENST00000367649.8	NP_733793.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASAL2	ENST00000367649.8	c.445G>A	p.Ala149Thr	missense_variant	Exon 3 of 18	1	NM_170692.4	ENSP00000356621.3
RASAL2	ENST00000696605.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 3 of 18			ENSP00000512749.1
RASAL2	ENST00000465723.1	n.*51G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249336 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460140 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726354

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 04, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.96
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.067
Sift	Benign	0.30	T
Sift4G	Benign	0.26	T
Vest4		0.20
MutPred		0.099		Gain of phosphorylation at A149 (P = 0.0104);
MVP		0.076
MPC		0.27
ClinPred		0.28	T
GERP RS		-0.52
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1038193873; hg19: chr1-178269241;