Genetic Variant NM_001098531.4:c.1155-93G>A (chr12-47748635-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001098531.4(RAPGEF3):c.1155-93G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,240,888 control chromosomes in the GnomAD database, including 16 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 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 16 hom. )

Consequence

RAPGEF3
NM_001098531.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.717

Publications

7 publications found

Variant links:

Genes affected

RAPGEF3 (HGNC:16629): (Rap guanine nucleotide exchange factor 3) Enables guanyl-nucleotide exchange factor activity and protein domain specific binding activity. Involved in several processes, including positive regulation of protein modification process; regulation of actin cytoskeleton organization; and regulation of syncytium formation by plasma membrane fusion. Located in filopodium; lamellipodium; and microvillus. Colocalizes with cortical actin cytoskeleton and plasma membrane. Biomarker of congestive heart failure. [provided by Alliance of Genome Resources, Apr 2022]

RAPGEF3 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=-0.89).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000668 (727/1088702) while in subpopulation AMR AF = 0.0189 (691/36482). AF 95% confidence interval is 0.0178. There are 16 homozygotes in GnomAdExome4. There are 295 alleles in the male GnomAdExome4 subpopulation. Median coverage is 14. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4 link	c.1155-93G>A		intron_variant	Intron 11 of 27	ENST00000449771.7	NP_001092001.2	Q99777

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAPGEF3	ENST00000449771.7 link	c.1155-93G>A	intron_variant	Intron 11 of 27	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 link	c.1155-93G>A	intron_variant	Intron 12 of 28	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000549151.5 link	c.1029-93G>A	intron_variant	Intron 11 of 27	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 link	c.1029-93G>A	intron_variant	Intron 11 of 26	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000395358.7 link	c.1155-93G>A	intron_variant	Intron 11 of 15	2		ENSP00000378764.3	O95398-2
RAPGEF3	ENST00000495465.6 link	n.*272-93G>A	intron_variant	Intron 6 of 8	3		ENSP00000449818.1	H0YIP6
RAPGEF3	ENST00000547856.5 link	n.*463-93G>A	intron_variant	Intron 7 of 23	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

AF:

0.000671

AC:

102

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD4 exome

AF:

0.000668

AC:

727

AN:

1088702

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

295

AN XY:

550804

show subpopulations

African (AFR)

AF:

0.0000382

AC:

AN:

26196

American (AMR)

AF:

0.0189

AC:

691

AN:

36482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21440

East Asian (EAS)

AF:

0.00

AC:

AN:

37110

South Asian (SAS)

AF:

0.00

AC:

AN:

72420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4952

European-Non Finnish (NFE)

AF:

0.00000884

AC:

AN:

792056

Other (OTH)

AF:

0.000588

AC:

AN:

47630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152186

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41496

American (AMR)

AF:

0.00549

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

2355

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.46

(source)

DANN

Benign

0.81

PhyloP100

-0.72

Mutation Taster

=100/0

polymorphism

(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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NM_001098531.4:c.1155-93G>A

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