Genetic Variant NM_001098531.4:c.108G>A (chr12-47757977-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_ModerateBP6_ModerateBP7

The NM_001098531.4(RAPGEF3):c.108G>A(p.Pro36Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,566,716 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

RAPGEF3
NM_001098531.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.59

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:

SLC48A1 (HGNC:26035): (solute carrier family 48 member 1) Enables heme binding activity and heme transmembrane transporter activity. Involved in heme transport. Located in endosome membrane; lysosomal membrane; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC48A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 12-47757977-C-T is Benign according to our data. Variant chr12-47757977-C-T is described in ClinVar as [Benign]. Clinvar id is 714536.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-3.59 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4 link	c.108G>A	p.Pro36Pro	synonymous_variant	Exon 2 of 28	ENST00000449771.7	NP_001092001.2	Q99777

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAPGEF3	ENST00000449771.7 link	c.108G>A	p.Pro36Pro	synonymous_variant	Exon 2 of 28	2	NM_001098531.4	ENSP00000395708.2	O95398-1
RAPGEF3	ENST00000389212.7 link	c.108G>A	p.Pro36Pro	synonymous_variant	Exon 3 of 29	2		ENSP00000373864.3	O95398-1
RAPGEF3	ENST00000395358.7 link	c.108G>A	p.Pro36Pro	synonymous_variant	Exon 2 of 16	2		ENSP00000378764.3	O95398-2
RAPGEF3	ENST00000549151.5 link	c.-19G>A		5_prime_UTR_variant	Exon 2 of 28	5		ENSP00000448619.1	O95398-3
RAPGEF3	ENST00000548919.5 link	c.-19G>A		5_prime_UTR_variant	Exon 2 of 27	2		ENSP00000448480.1	F8VRX1
RAPGEF3	ENST00000547856.5 link	n.108G>A		non_coding_transcript_exon_variant	Exon 2 of 24	2		ENSP00000449905.1	F8VVJ6

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

233

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000351

AC:

AN:

176752

AF XY:

0.000255

show subpopulations

Gnomad AFR exome

AF:

0.00406

Gnomad AMR exome

AF:

0.000667

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000150

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000152

AC:

215

AN:

1414416

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

101

AN XY:

699152

show subpopulations

African (AFR)

AF:

0.00475

AC:

154

AN:

32436

American (AMR)

AF:

0.000501

AC:

AN:

37932

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25272

East Asian (EAS)

AF:

0.0000807

AC:

AN:

37194

South Asian (SAS)

AF:

0.0000249

AC:

AN:

80412

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49808

Middle Eastern (MID)

AF:

0.000363

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.0000101

AC:

AN:

1087250

Other (OTH)

AF:

0.000393

AC:

AN:

58596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00154

AC:

235

AN:

152300

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00534

AC:

222

AN:

41566

American (AMR)

AF:

0.000849

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000834

Hom.:

Bravo

AF:

0.00178

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 15, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

1.2

(source)

DANN

Benign

0.91

PhyloP100

-3.6

PromoterAI

-0.025

Neutral

(source)

Mutation Taster

=297/3

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

Loading publications...

NM_001098531.4:c.108G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over