rs7976407

Variant names:

• chr12-113130992-A-G
• rs7976407
• NM_001301202.2:c.66-51T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001301202.2(RASAL1):​c.66-51T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,440,484 control chromosomes in the GnomAD database, including 10,189 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.14 (1668 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8521 hom.)
• Consequence: RASAL1 NM_001301202.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.49
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASAL1	NM_001301202.2	c.66-51T>C		intron_variant	Intron 1 of 20	ENST00000548055.2	NP_001288131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASAL1	ENST00000548055.2	c.66-51T>C		intron_variant	Intron 1 of 20	1	NM_001301202.2	ENSP00000448510.1

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20498 AN: 151884 Hom.: 1651 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0838

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.123 AC: 28813 AN: 234592 AF XY: 0.124

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.217

Gnomad FIN exome AF: 0.0959

Gnomad NFE exome AF: 0.0840

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.104 AC: 134572 AN: 1288482 Hom.: 8521 Cov.: 18 AF XY: 0.107 AC XY: 69389 AN XY: 648402

African (AFR) AF: 0.228 AC: 6847 AN: 30008

American (AMR) AF: 0.0985 AC: 4253 AN: 43190

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2832 AN: 24552

East Asian (EAS) AF: 0.236 AC: 9175 AN: 38814

South Asian (SAS) AF: 0.197 AC: 15923 AN: 80716

European-Finnish (FIN) AF: 0.0953 AC: 4885 AN: 51252

Middle Eastern (MID) AF: 0.109 AC: 594 AN: 5446

European-Non Finnish (NFE) AF: 0.0868 AC: 83281 AN: 959894

Other (OTH) AF: 0.124 AC: 6782 AN: 54610

GnomAD4 genome AF: 0.135 AC: 20550 AN: 152002 Hom.: 1668 Cov.: 31 AF XY: 0.137 AC XY: 10201 AN XY: 74286

African (AFR) AF: 0.224 AC: 9269 AN: 41414

American (AMR) AF: 0.104 AC: 1590 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 398 AN: 3470

East Asian (EAS) AF: 0.214 AC: 1103 AN: 5146

South Asian (SAS) AF: 0.206 AC: 992 AN: 4814

European-Finnish (FIN) AF: 0.105 AC: 1109 AN: 10592

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0837 AC: 5692 AN: 67974

Other (OTH) AF: 0.117 AC: 247 AN: 2108

Alfa AF: 0.105 Hom.: 1780

Bravo AF: 0.138

Asia WGS AF: 0.242 AC: 839 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.26
DANN	Benign	0.46
PhyloP100		-2.5
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs7976407; hg19: chr12-113568797; COSMIC: COSV55658320;