Genetic Variant RASGEF1C:p.Ala382Thr (chr5-180114481-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_175062.4(RASGEF1C):c.1144G>A(p.Ala382Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000825 in 1,612,850 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000082 ( 3 hom. )

Consequence

RASGEF1C
NM_175062.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

Publications

0 publications found

Variant links:

Genes affected

RASGEF1C (HGNC:27400): (RasGEF domain family member 1C) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity and small GTPase mediated signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

RASGEF1C links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07534662).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175062.4. 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
	RASGEF1C	NM_175062.4	MANE Select	c.1144G>A	p.Ala382Thr	missense	Exon 11 of 14	NP_778232.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASGEF1C	ENST00000361132.9	TSL:1 MANE Select	c.1144G>A	p.Ala382Thr	missense	Exon 11 of 14	ENSP00000354963.4	Q8N431-1
RASGEF1C	ENST00000393371.6	TSL:1	c.1144G>A	p.Ala382Thr	missense	Exon 10 of 13	ENSP00000377037.2	Q8N431-1
RASGEF1C	ENST00000923269.1		c.1144G>A	p.Ala382Thr	missense	Exon 12 of 15	ENSP00000593328.1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251308

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000822

AC:

120

AN:

1460538

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726542

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33450

American (AMR)

AF:

0.000179

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.000101

AC:

AN:

39656

South Asian (SAS)

AF:

0.000685

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1111124

Other (OTH)

AF:

0.000182

AC:

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41578

American (AMR)

AF:

0.000392

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000115

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.025

Eigen

Benign

-0.16

Eigen_PC

Benign

0.0086

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.013

MetaRNN

Benign

0.075

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.79

PhyloP100

3.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.1

REVEL

Benign

0.094

Sift

Benign

0.72

Sift4G

Benign

0.44

Polyphen

0.094

Vest4

0.22

MVP

0.37

MPC

0.52

ClinPred

0.027

GERP RS

4.6

Varity_R

0.074

gMVP

0.46

Mutation Taster

=66/34

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over