12-113104048-A-G

Variant names:

• chr12-113104048-A-G
• rs1592883978
• NM_001301202.2:c.2002T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001301202.2(RASAL1):​c.2002T>C​(p.Leu668Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 1,358,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: RASAL1 NM_001301202.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.874
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=0.874 with no splicing effect.

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.2002T>C	p.Leu668Leu	synonymous	Exon 18 of 21	NP_001288131.1	O95294-4
	RASAL1	NM_001193520.2		c.2005T>C	p.Leu669Leu	synonymous	Exon 19 of 22	NP_001180449.1	O95294-3
	RASAL1	NM_001394081.1		c.2005T>C	p.Leu669Leu	synonymous	Exon 18 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.2002T>C	p.Leu668Leu	synonymous	Exon 18 of 21	ENSP00000448510.1	O95294-4
	RASAL1	ENST00000546530.5	TSL:1	c.2005T>C	p.Leu669Leu	synonymous	Exon 19 of 22	ENSP00000450244.1	O95294-3
	RASAL1	ENST00000261729.9	TSL:1	c.1999T>C	p.Leu667Leu	synonymous	Exon 19 of 22	ENSP00000261729.5	O95294-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000221 AC: 3 AN: 1358164 Hom.: 0 Cov.: 32 AF XY: 0.00000299 AC XY: 2 AN XY: 668080

African (AFR) AF: 0.00 AC: 0 AN: 30686

American (AMR) AF: 0.00 AC: 0 AN: 39104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21764

East Asian (EAS) AF: 0.00 AC: 0 AN: 34246

South Asian (SAS) AF: 0.0000376 AC: 3 AN: 79704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047624

Other (OTH) AF: 0.00 AC: 0 AN: 53998

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		0.87

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

Other links and lift over

dbSNP: rs1592883978; hg19: chr12-113541853;