12-121921519-A-T

Variant names:

• chr12-121921519-A-T
• rs749949583
• NM_144668.6:c.214A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144668.6(CFAP251):​c.214A>T​(p.Ile72Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I72V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFAP251 NM_144668.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.22
• Publications: 0 publications found

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

ENSG00000256950 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056706905).

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.214A>T	p.Ile72Phe	missense	Exon 2 of 22	NP_653269.3	Q8TBY9-1
	CFAP251	NM_001178003.2		c.214A>T	p.Ile72Phe	missense	Exon 2 of 18	NP_001171474.1	Q8TBY9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP251	ENST00000288912.9	TSL:1 MANE Select	c.214A>T	p.Ile72Phe	missense	Exon 2 of 22	ENSP00000288912.4	Q8TBY9-1
	CFAP251	ENST00000397454.2	TSL:1	c.214A>T	p.Ile72Phe	missense	Exon 2 of 18	ENSP00000380595.2	Q8TBY9-2
	CFAP251	ENST00000880754.1		c.214A>T	p.Ile72Phe	missense	Exon 2 of 22	ENSP00000550813.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.0
DANN	Benign	0.89
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.00088	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.99	T
PhyloP100		-2.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.030
Sift	Benign	0.058	T
Sift4G	Benign	0.10	T
Polyphen		0.013	B
Vest4		0.14
MutPred		0.17		Gain of helix (P = 0.005)
MVP		0.014
MPC		0.22
ClinPred		0.033	T
GERP RS		-1.5
Varity_R		0.059
gMVP		0.028
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs749949583; hg19: chr12-122359425;