Genetic Variant NM_145313.4:c.631G>T (chr10-43200717-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_145313.4(RASGEF1A):c.631G>T(p.Val211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V211M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RASGEF1A
NM_145313.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.81

Publications

5 publications found

Variant links:

Genes affected

RASGEF1A (HGNC:24246): (RasGEF domain family member 1A) Enables guanyl-nucleotide exchange factor activity. Involved in cell migration and positive regulation of Ras protein signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

RASGEF1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26670808).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145313.4. 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
	RASGEF1A	NM_145313.4	MANE Select	c.631G>T	p.Val211Leu	missense	Exon 5 of 13	NP_660356.2	Q8N9B8-1
	RASGEF1A	NM_001282862.2		c.655G>T	p.Val219Leu	missense	Exon 5 of 13	NP_001269791.1	Q8N9B8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGEF1A	ENST00000395810.6	TSL:1 MANE Select	c.631G>T	p.Val211Leu	missense	Exon 5 of 13	ENSP00000379155.1	Q8N9B8-1
RASGEF1A	ENST00000954344.1		c.667G>T	p.Val223Leu	missense	Exon 5 of 13	ENSP00000624403.1
RASGEF1A	ENST00000374459.5	TSL:2	c.655G>T	p.Val219Leu	missense	Exon 5 of 13	ENSP00000363583.1	Q8N9B8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461256

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.023

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0082

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.48

PhyloP100

1.8

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Benign

0.35

Sift4G

Benign

0.32

Polyphen

0.023

Vest4

0.36

MutPred

0.51

Gain of sheet (P = 0.0344)

MVP

0.28

MPC

0.73

ClinPred

0.74

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.79

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over