12-113105737-A-G

Position:

• chr12-113105737-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001301202.2(RASAL1):​c.1807T>C​(p.Phe603Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,611,626 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (16 hom.)
• Consequence: RASAL1 NM_001301202.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.74

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010164529).
• BP6: Variant 12-113105737-A-G is Benign according to our data. Variant chr12-113105737-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 218644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASAL1	NM_001301202.2	c.1807T>C	p.Phe603Leu	missense_variant	16/21	ENST00000548055.2	NP_001288131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASAL1	ENST00000548055.2	c.1807T>C	p.Phe603Leu	missense_variant	16/21	1	NM_001301202.2	ENSP00000448510.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152270 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00245 AC: 611 AN: 249398 Hom.: 2 AF XY: 0.00283 AC XY: 382 AN XY: 134768

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.00493

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00454

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00240 AC: 3502 AN: 1459238 Hom.: 16 Cov.: 31 AF XY: 0.00250 AC XY: 1816 AN XY: 725658

Gnomad4 AFR exome AF: 0.000719

Gnomad4 AMR exome AF: 0.00247

Gnomad4 ASJ exome AF: 0.00484

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00446

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00304

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152388 Hom.: 0 Cov.: 34 AF XY: 0.00187 AC XY: 139 AN XY: 74524

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00269

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00250 Hom.: 3

Bravo AF: 0.00211

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00259 AC: 315

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00428

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	RASAL1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 03, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jun 19, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T;.;.
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.1	.;L;L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.14, 0.024	.;B;B;.
Vest4		0.39
MutPred		0.36		.;Loss of catalytic residue at F602 (P = 0.0735);Loss of catalytic residue at F602 (P = 0.0735);.;
MVP		0.92
MPC		0.34
ClinPred		0.017	T
GERP RS		5.4
Varity_R		0.48
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs142556970; hg19: chr12-113543542;