Genetic Variant NM_001145648.3:c.3495-104C>T (chr15-78973524-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001145648.3(RASGRF1):c.3495-104C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 805,412 control chromosomes in the GnomAD database, including 39,393 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.

Frequency

Genomes: 𝑓 0.28 ( 6371 hom., cov: 32)

Exomes 𝑓: 0.31 ( 33022 hom. )

Consequence

RASGRF1
NM_001145648.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.420

Publications

7 publications found

Variant links:

Genes affected

RASGRF1 (HGNC:9875): (Ras protein specific guanine nucleotide releasing factor 1) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) similar to the Saccharomyces cerevisiae CDC25 gene product. Functional analysis has demonstrated that this protein stimulates the dissociation of GDP from RAS protein. The studies of the similar gene in mouse suggested that the Ras-GEF activity of this protein in brain can be activated by Ca2+ influx, muscarinic receptors, and G protein beta-gamma subunit. Mouse studies also indicated that the Ras-GEF signaling pathway mediated by this protein may be important for long-term memory. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Mar 2009]

RASGRF1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASGRF1	NM_001145648.3 link	c.3495-104C>T		intron_variant	Intron 24 of 26	ENST00000558480.7	NP_001139120.1	Q8IUU5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RASGRF1	ENST00000558480.7 link	c.3495-104C>T	intron_variant	Intron 24 of 26	2	NM_001145648.3	ENSP00000452781.2	Q13972-3
RASGRF1	ENST00000394745.3 link	c.1191-104C>T	intron_variant	Intron 11 of 13	1		ENSP00000378228.3	Q13972-2
RASGRF1	ENST00000419573.7 link	c.3543-104C>T	intron_variant	Intron 25 of 27	2		ENSP00000405963.3	Q13972-1
RASGRF1	ENST00000559926.1 link	n.199-104C>T	intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42008

AN:

151888

Hom.:

6371

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.157

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.339

Gnomad OTH

AF:

0.276

GnomAD4 exome

AF:

0.312

AC:

203539

AN:

653406

Hom.:

33022

AF XY:

0.309

AC XY:

105816

AN XY:

342328

show subpopulations

African (AFR)

AF:

0.166

AC:

2737

AN:

16484

American (AMR)

AF:

0.317

AC:

8997

AN:

28404

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

4447

AN:

15794

East Asian (EAS)

AF:

0.170

AC:

5789

AN:

34104

South Asian (SAS)

AF:

0.250

AC:

14063

AN:

56200

European-Finnish (FIN)

AF:

0.341

AC:

15733

AN:

46082

Middle Eastern (MID)

AF:

0.283

AC:

1117

AN:

3950

European-Non Finnish (NFE)

AF:

0.335

AC:

140645

AN:

419806

Other (OTH)

AF:

0.307

AC:

10011

AN:

32582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

6562

13123

19685

26246

32808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2306

4612

6918

9224

11530

<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:

0.276

AC:

42011

AN:

152006

Hom.:

6371

Cov.:

AF XY:

0.273

AC XY:

20286

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.168

AC:

6978

AN:

41464

American (AMR)

AF:

0.295

AC:

4508

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

968

AN:

3468

East Asian (EAS)

AF:

0.157

AC:

811

AN:

5160

South Asian (SAS)

AF:

0.253

AC:

1215

AN:

4810

European-Finnish (FIN)

AF:

0.344

AC:

3632

AN:

10558

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.339

AC:

23021

AN:

67954

Other (OTH)

AF:

0.275

AC:

581

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1529

3057

4586

6114

7643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.316

Hom.:

9503

Bravo

AF:

0.271

Asia WGS

AF:

0.193

AC:

673

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.6

(source)

DANN

Benign

0.86

PhyloP100

0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over