Genetic Variant NM_016340.6:c.352-113A>C (chr5-131548303-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_016340.6(RAPGEF6):c.352-113A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 1,055,606 control chromosomes in the GnomAD database, including 2,503 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 0.051 ( 269 hom., cov: 31)

Exomes 𝑓: 0.064 ( 2234 hom. )

Consequence

RAPGEF6
NM_016340.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0640

Publications

5 publications found

Variant links:

Genes affected

RAPGEF6 (HGNC:20655): (Rap guanine nucleotide exchange factor 6) Enables several functions, including GTP-dependent protein binding activity; guanyl-nucleotide exchange factor activity; and phosphatidic acid binding activity. Involved in microvillus assembly; positive regulation of GTPase activity; and protein localization to plasma membrane. Located in several cellular components, including apical plasma membrane; centrosome; and endocytic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

RAPGEF6 links:

ENSG00000273217 (HGNC:):

ENSG00000273217 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=-0.78).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016340.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RAPGEF6	NM_016340.6	MANE Select	c.352-113A>C	intron	N/A	NP_057424.3
RAPGEF6	NM_001164386.2		c.352-113A>C	intron	N/A	NP_001157858.1
RAPGEF6	NM_001164387.2		c.352-113A>C	intron	N/A	NP_001157859.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RAPGEF6	ENST00000509018.6	TSL:1 MANE Select	c.352-113A>C	intron	N/A	ENSP00000421684.1
ENSG00000273217	ENST00000514667.1	TSL:2	c.502-113A>C	intron	N/A	ENSP00000426948.1
RAPGEF6	ENST00000296859.10	TSL:1	c.352-113A>C	intron	N/A	ENSP00000296859.6

Frequencies

GnomAD3 genomes

AF:

0.0513

AC:

7804

AN:

152158

Hom.:

268

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.0332

Gnomad ASJ

AF:

0.0920

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0470

Gnomad FIN

AF:

0.0739

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0771

Gnomad OTH

AF:

0.0469

GnomAD4 exome

AF:

0.0644

AC:

58199

AN:

903330

Hom.:

2234

AF XY:

0.0643

AC XY:

29481

AN XY:

458338

show subpopulations

African (AFR)

AF:

0.0108

AC:

228

AN:

21188

American (AMR)

AF:

0.0249

AC:

588

AN:

23630

Ashkenazi Jewish (ASJ)

AF:

0.0974

AC:

1701

AN:

17456

East Asian (EAS)

AF:

0.000484

AC:

AN:

35090

South Asian (SAS)

AF:

0.0430

AC:

2473

AN:

57514

European-Finnish (FIN)

AF:

0.0724

AC:

2782

AN:

38420

Middle Eastern (MID)

AF:

0.0349

AC:

115

AN:

3292

European-Non Finnish (NFE)

AF:

0.0720

AC:

47869

AN:

665270

Other (OTH)

AF:

0.0585

AC:

2426

AN:

41470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2638

5275

7913

10550

13188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1408

2816

4224

5632

7040

<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:

0.0513

AC:

7806

AN:

152276

Hom.:

269

Cov.:

AF XY:

0.0505

AC XY:

3763

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0132

AC:

547

AN:

41574

American (AMR)

AF:

0.0331

AC:

507

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0920

AC:

319

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0477

AC:

230

AN:

4826

European-Finnish (FIN)

AF:

0.0739

AC:

784

AN:

10610

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0770

AC:

5239

AN:

67996

Other (OTH)

AF:

0.0464

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

373

747

1120

1494

1867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0616

Hom.:

259

Bravo

AF:

0.0457

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.9

(source)

DANN

Benign

0.66

PhyloP100

0.064

Mutation Taster

=100/0

polymorphism (auto)

(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