12-121921636-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PVS1PP5_ModerateBS2_Supporting

The NM_144668.6(CFAP251):c.331G>T(p.Glu111*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,612,264 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0022 ( 6 hom. )

Consequence

CFAP251
NM_144668.6 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:4

Conservation

PhyloP100: 0.367

Publications

14 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:

ENSG00000256950 (HGNC:):

ENSG00000256950 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 12-121921636-G-T is Pathogenic according to our data. Variant chr12-121921636-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548449.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144668.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP251	NM_144668.6	MANE Select	c.331G>T	p.Glu111*	stop_gained	Exon 2 of 22	NP_653269.3	Q8TBY9-1
	CFAP251	NM_001178003.2		c.331G>T	p.Glu111*	stop_gained	Exon 2 of 18	NP_001171474.1	Q8TBY9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFAP251	ENST00000288912.9	TSL:1 MANE Select	c.331G>T	p.Glu111*	stop_gained	Exon 2 of 22	ENSP00000288912.4	Q8TBY9-1
CFAP251	ENST00000397454.2	TSL:1	c.331G>T	p.Glu111*	stop_gained	Exon 2 of 18	ENSP00000380595.2	Q8TBY9-2
CFAP251	ENST00000880754.1		c.331G>T	p.Glu111*	stop_gained	Exon 2 of 22	ENSP00000550813.1

Frequencies

GnomAD3 genomes

AF:

0.000979

AC:

149

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00100

AC:

248

AN:

247336

AF XY:

0.000998

show subpopulations

Gnomad AFR exome

AF:

0.000648

Gnomad AMR exome

AF:

0.000560

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000372

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.00216

AC:

3154

AN:

1459996

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

1513

AN XY:

726252

show subpopulations

African (AFR)

AF:

0.000420

AC:

AN:

33348

American (AMR)

AF:

0.000588

AC:

AN:

44184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000361

AC:

AN:

85772

European-Finnish (FIN)

AF:

0.000562

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00265

AC:

2950

AN:

1111464

Other (OTH)

AF:

0.00171

AC:

103

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.000979

AC:

149

AN:

152268

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41558

American (AMR)

AF:

0.000589

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68014

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00162

Hom.:

Bravo

AF:

0.00120

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00102

AC:

ESP6500EA

AF:

0.00180

AC:

ExAC

AF:

0.00116

AC:

140

EpiCase

AF:

0.00153

EpiControl

AF:

0.00160

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spermatogenic failure 33 (3)

Non-syndromic male infertility due to sperm motility disorder;C4706677:Male infertility with teratozoospermia due to single gene mutation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.070

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.090

PhyloP100

0.37

Vest4

0.034

GERP RS

2.0

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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