Genetic Variant NM_001200049.3:c.6745G>A (chr10-132834775-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001200049.3(CFAP46):c.6745G>A(p.Glu2249Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 1,609,360 control chromosomes in the GnomAD database, including 3,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.052 ( 279 hom., cov: 34)

Exomes 𝑓: 0.067 ( 3571 hom. )

Consequence

CFAP46
NM_001200049.3 missense, splice_region

Scores

Splicing: ADA: 0.009252

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.226

Publications

11 publications found

Variant links:

Genes affected

CFAP46 (HGNC:25247): (cilia and flagella associated protein 46) Predicted to be involved in axoneme assembly. Predicted to be located in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

CFAP46 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0035960674).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP46	NM_001200049.3 link	c.6745G>A	p.Glu2249Lys	missense_variant, splice_region_variant	Exon 48 of 58	ENST00000368586.10	NP_001186978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CFAP46	ENST00000368586.10 link	c.6745G>A	p.Glu2249Lys	missense_variant, splice_region_variant	Exon 48 of 58	5	NM_001200049.3	ENSP00000357575.4
CFAP46	ENST00000639072.2 link	c.6745G>A	p.Glu2249Lys	missense_variant, splice_region_variant	Exon 48 of 59	5		ENSP00000491877.2
CFAP46	ENST00000448925.1 link	c.49G>A	p.Glu17Lys	missense_variant, splice_region_variant	Exon 2 of 5	3		ENSP00000417039.1
CFAP46	ENST00000476633.1 link	n.470G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.0520

AC:

7912

AN:

152192

Hom.:

277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.0835

Gnomad AMR

AF:

0.0317

Gnomad ASJ

AF:

0.0467

Gnomad EAS

AF:

0.0613

Gnomad SAS

AF:

0.0429

Gnomad FIN

AF:

0.0998

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0742

Gnomad OTH

AF:

0.0392

GnomAD2 exomes

AF:

0.0580

AC:

14239

AN:

245662

AF XY:

0.0591

show subpopulations

Gnomad AFR exome

AF:

0.00961

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0469

Gnomad EAS exome

AF:

0.0628

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.0721

Gnomad OTH exome

AF:

0.0582

GnomAD4 exome

AF:

0.0669

AC:

97479

AN:

1457050

Hom.:

3571

Cov.:

AF XY:

0.0666

AC XY:

48225

AN XY:

724132

show subpopulations

African (AFR)

AF:

0.00900

AC:

300

AN:

33342

American (AMR)

AF:

0.0240

AC:

1070

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.0489

AC:

1273

AN:

26046

East Asian (EAS)

AF:

0.0712

AC:

2816

AN:

39570

South Asian (SAS)

AF:

0.0419

AC:

3605

AN:

86066

European-Finnish (FIN)

AF:

0.104

AC:

5507

AN:

52810

Middle Eastern (MID)

AF:

0.0202

AC:

109

AN:

5396

European-Non Finnish (NFE)

AF:

0.0712

AC:

79014

AN:

1109224

Other (OTH)

AF:

0.0630

AC:

3785

AN:

60104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

4916

9832

14747

19663

24579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2836

5672

8508

11344

14180

<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:

0.0520

AC:

7914

AN:

152310

Hom.:

279

Cov.:

AF XY:

0.0527

AC XY:

3925

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0114

AC:

475

AN:

41584

American (AMR)

AF:

0.0316

AC:

484

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0467

AC:

162

AN:

3472

East Asian (EAS)

AF:

0.0616

AC:

318

AN:

5162

South Asian (SAS)

AF:

0.0429

AC:

207

AN:

4826

European-Finnish (FIN)

AF:

0.0998

AC:

1060

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0742

AC:

5046

AN:

68018

Other (OTH)

AF:

0.0388

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

402

803

1205

1606

2008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0641

Hom.:

751

Bravo

AF:

0.0442

TwinsUK

AF:

0.0677

AC:

251

ALSPAC

AF:

0.0693

AC:

267

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.0688

AC:

592

ExAC

AF:

0.0586

AC:

7113

Asia WGS

AF:

0.0370

AC:

128

AN:

3478

EpiCase

AF:

0.0649

EpiControl

AF:

0.0646

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.55

CADD

Benign

4.1

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0088

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.52

M_CAP

Benign

0.0036

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.98

PhyloP100

-0.23

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.70

REVEL

Benign

0.029

Sift

Benign

0.36

Sift4G

Uncertain

0.019

Vest4

0.050

MPC

0.18

ClinPred

0.0046

GERP RS

-1.6

Varity_R

0.090

gMVP

0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0093

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.080

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