NM_001301202.2:c.1901C>T

Variant names:

• chr12-113104228-G-A
• NM_001301202.2:c.1901C>T

Variant summary

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

The NM_001301202.2(RASAL1):​c.1901C>T​(p.Pro634Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RASAL1 NM_001301202.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49
• Publications: 0 publications found

Genes affected

RASAL1 (HGNC:9873): (RAS protein activator like 1) The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. These proteins stimulate the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. This particular family member contains domains which are characteristic of the GAP1 subfamily of RasGAP proteins but, in contrast to the other GAP1 family members, this protein is strongly and selectively expressed in endocrine tissues. Alternatively spliced transcript variants that encode different isoforms have been described [provided by RefSeq, Jul 2010]

RASAL1 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000295497 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301202.2. 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
	RASAL1	NM_001301202.2	MANE Select	c.1901C>T	p.Pro634Leu	missense	Exon 17 of 21	NP_001288131.1	O95294-4
	RASAL1	NM_001193520.2		c.1904C>T	p.Pro635Leu	missense	Exon 18 of 22	NP_001180449.1	O95294-3
	RASAL1	NM_001394081.1		c.1904C>T	p.Pro635Leu	missense	Exon 17 of 21	NP_001381010.1	O95294-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASAL1	ENST00000548055.2	TSL:1 MANE Select	c.1901C>T	p.Pro634Leu	missense	Exon 17 of 21	ENSP00000448510.1	O95294-4
	RASAL1	ENST00000546530.5	TSL:1	c.1904C>T	p.Pro635Leu	missense	Exon 18 of 22	ENSP00000450244.1	O95294-3
	RASAL1	ENST00000261729.9	TSL:1	c.1898C>T	p.Pro633Leu	missense	Exon 18 of 22	ENSP00000261729.5	O95294-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455920 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 723698

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 43836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 85230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109744

Other (OTH) AF: 0.00 AC: 0 AN: 60094

GnomAD4 genome Cov.: 33

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	0.11
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.5
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.52
Sift	Benign	0.042	D
Sift4G	Uncertain	0.042	D
Polyphen		0.42	B
Vest4		0.53
MutPred		0.58		Gain of sheet (P = 0.0827)
MVP		0.93
MPC		2.8
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.20
gMVP		0.28
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

hg19: chr12-113542033;