NM_144668.6:c.919G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144668.6(CFAP251):c.919G>A(p.Val307Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,612,296 control chromosomes in the GnomAD database, including 2,057 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 134 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1923 hom. )

Consequence

CFAP251
NM_144668.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.106

Publications

12 publications found

Variant links:

Genes affected

CFAP251 (HGNC:28506): (cilia and flagella associated protein 251) This protein encoded by this gene belongs to the WD repeat-containing family of proteins, which function in the formation of protein-protein complexes in a variety of biological pathways. This family member appears to function in the determination of mean platelet volume (MPV), and polymorphisms in this gene have been associated with variance in MPV. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2011]

CFAP251 Gene-Disease associations (from GenCC):

spermatogenic failure 33
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
non-syndromic male infertility due to sperm motility disorder
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CFAP251 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033690035).

BP6

Variant 12-121934277-G-A is Benign according to our data. Variant chr12-121934277-G-A is described in ClinVar as Benign. ClinVar VariationId is 403606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP251	NM_144668.6 link	c.919G>A	p.Val307Ile	missense_variant	Exon 5 of 22	ENST00000288912.9	NP_653269.3	Q8TBY9-1
CFAP251	NM_001178003.2 link	c.919G>A	p.Val307Ile	missense_variant	Exon 5 of 18		NP_001171474.1	Q8TBY9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CFAP251	ENST00000288912.9 link	c.919G>A	p.Val307Ile	missense_variant	Exon 5 of 22	1	NM_144668.6	ENSP00000288912.4	Q8TBY9-1
CFAP251	ENST00000397454.2 link	c.919G>A	p.Val307Ile	missense_variant	Exon 5 of 18	1		ENSP00000380595.2	Q8TBY9-2
CFAP251	ENST00000546044.1 link	n.28G>A		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0363

AC:

5521

AN:

152146

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00948

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.0923

Gnomad EAS

AF:

0.0370

Gnomad SAS

AF:

0.0536

Gnomad FIN

AF:

0.0254

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0493

Gnomad OTH

AF:

0.0449

GnomAD2 exomes

AF:

0.0419

AC:

10450

AN:

249180

AF XY:

0.0436

show subpopulations

Gnomad AFR exome

AF:

0.00905

Gnomad AMR exome

AF:

0.0279

Gnomad ASJ exome

AF:

0.0863

Gnomad EAS exome

AF:

0.0303

Gnomad FIN exome

AF:

0.0270

Gnomad NFE exome

AF:

0.0483

Gnomad OTH exome

AF:

0.0457

GnomAD4 exome

AF:

0.0469

AC:

68464

AN:

1460032

Hom.:

1923

Cov.:

AF XY:

0.0472

AC XY:

34280

AN XY:

726384

show subpopulations

African (AFR)

AF:

0.00837

AC:

280

AN:

33470

American (AMR)

AF:

0.0289

AC:

1291

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0856

AC:

2236

AN:

26118

East Asian (EAS)

AF:

0.0446

AC:

1772

AN:

39688

South Asian (SAS)

AF:

0.0516

AC:

4451

AN:

86210

European-Finnish (FIN)

AF:

0.0274

AC:

1464

AN:

53340

Middle Eastern (MID)

AF:

0.0496

AC:

286

AN:

5764

European-Non Finnish (NFE)

AF:

0.0485

AC:

53826

AN:

1110420

Other (OTH)

AF:

0.0474

AC:

2858

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

3048

6096

9144

12192

15240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2056

4112

6168

8224

10280

<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:

0.0363

AC:

5532

AN:

152264

Hom.:

134

Cov.:

AF XY:

0.0355

AC XY:

2645

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00948

AC:

394

AN:

41564

American (AMR)

AF:

0.0406

AC:

621

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0923

AC:

320

AN:

3468

East Asian (EAS)

AF:

0.0369

AC:

191

AN:

5182

South Asian (SAS)

AF:

0.0539

AC:

260

AN:

4826

European-Finnish (FIN)

AF:

0.0254

AC:

270

AN:

10614

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0493

AC:

3355

AN:

68000

Other (OTH)

AF:

0.0497

AC:

105

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

259

519

778

1038

1297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0473

Hom.:

646

Bravo

AF:

0.0347

TwinsUK

AF:

0.0502

AC:

186

ALSPAC

AF:

0.0493

AC:

190

ESP6500AA

AF:

0.00981

AC:

ESP6500EA

AF:

0.0455

AC:

380

ExAC

AF:

0.0421

AC:

5092

Asia WGS

AF:

0.0680

AC:

238

AN:

3478

EpiCase

AF:

0.0442

EpiControl

AF:

0.0463

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.21

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0073

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.1

PhyloP100

0.11

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.23

Sift

Benign

0.25

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.013

B;.

Vest4

0.048

MPC

0.11

ClinPred

0.0025

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over