12-121921636-G-T

Position:

• chr12-121921636-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PVS1 PP5 BS2_Supporting

The NM_144668.6(CFAP251):​c.331G>T​(p.Glu111Ter) 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 Pathogenic (no stars). 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
• Clinical Significance: Pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 0.367

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 [Pathogenic]. Clinvar id is 548449.Status of the report is no_assertion_criteria_provided, 0 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP251	NM_144668.6	c.331G>T	p.Glu111Ter	stop_gained	2/22	ENST00000288912.9	NP_653269.3
CFAP251	NM_001178003.2	c.331G>T	p.Glu111Ter	stop_gained	2/18		NP_001171474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP251	ENST00000288912.9	c.331G>T	p.Glu111Ter	stop_gained	2/22	1	NM_144668.6	ENSP00000288912
CFAP251	ENST00000397454.2	c.331G>T	p.Glu111Ter	stop_gained	2/18	1		ENSP00000380595	P1
CFAP251	ENST00000540779.1	n.229G>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152150 Hom.: 1 Cov.: 31

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

GnomAD3 exomes AF: 0.00100 AC: 248 AN: 247336 Hom.: 0 AF XY: 0.000998 AC XY: 134 AN XY: 134204

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 SAS exome AF: 0.000233

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.: 6 Cov.: 37 AF XY: 0.00208 AC XY: 1513 AN XY: 726252

Gnomad4 AFR exome AF: 0.000420

Gnomad4 AMR exome AF: 0.000588

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000361

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00265

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.000979 AC: 149 AN: 152268 Hom.: 1 Cov.: 31 AF XY: 0.000819 AC XY: 61 AN XY: 74458

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00102 AC: 4

ESP6500EA AF: 0.00180 AC: 15

ExAC AF: 0.00116 AC: 140

EpiCase AF: 0.00153

EpiControl AF: 0.00160

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 33 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 24, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 04, 2024	- -

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

Pathogenic, no assertion criteria provided

clinical testing

Marseille Medical Genetics, U1251, Aix Marseille University, Inserm

Jun 29, 2018

Bialleleic rare loss-of-function variants in WDR66 have been described in two independent cases of asthenozoospermia with multiple morphologic abnormalities of the sperm flagellum. One of these cases is a compound heterozygote for p.Leu530Valfs*4 and a nonsense variant p.Glu111*. In this case a dysplasia of the mitochondrial sheath was described by immunofluorescence and electron microscopy (Auguste et al. 2018, article in revision). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Benign	0.070
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.090	N
MutationTaster	Benign	1.0	A;A
Vest4		0.034
GERP RS		2.0

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

LitVar

Other links and lift over

dbSNP: rs199671406; hg19: chr12-122359542;