chr12-121934277-G-A

Position:

• chr12-121934277-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.106

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 Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
CFAP251	NM_144668.6	c.919G>A	p.Val307Ile	missense_variant	5/22	ENST00000288912.9	NP_653269.3
CFAP251	NM_001178003.2	c.919G>A	p.Val307Ile	missense_variant	5/18		NP_001171474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP251	ENST00000288912.9	c.919G>A	p.Val307Ile	missense_variant	5/22	1	NM_144668.6	ENSP00000288912
CFAP251	ENST00000397454.2	c.919G>A	p.Val307Ile	missense_variant	5/18	1		ENSP00000380595	P1
CFAP251	ENST00000546044.1	n.28G>A		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5521 AN: 152146 Hom.: 132 Cov.: 32

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

GnomAD3 exomes AF: 0.0419 AC: 10450 AN: 249180 Hom.: 270 AF XY: 0.0436 AC XY: 5895 AN XY: 135168

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 SAS exome AF: 0.0529

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.: 30 AF XY: 0.0472 AC XY: 34280 AN XY: 726384

Gnomad4 AFR exome AF: 0.00837

Gnomad4 AMR exome AF: 0.0289

Gnomad4 ASJ exome AF: 0.0856

Gnomad4 EAS exome AF: 0.0446

Gnomad4 SAS exome AF: 0.0516

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0485

Gnomad4 OTH exome AF: 0.0474

GnomAD4 genome AF: 0.0363 AC: 5532 AN: 152264 Hom.: 134 Cov.: 32 AF XY: 0.0355 AC XY: 2645 AN XY: 74460

Gnomad4 AFR AF: 0.00948

Gnomad4 AMR AF: 0.0406

Gnomad4 ASJ AF: 0.0923

Gnomad4 EAS AF: 0.0369

Gnomad4 SAS AF: 0.0539

Gnomad4 FIN AF: 0.0254

Gnomad4 NFE AF: 0.0493

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0484 Hom.: 336

Bravo AF: 0.0347

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.00981 AC: 40

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

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.21
DANN	Benign	0.91
DEOGEN2	Benign	0.0073	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
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	T
GERP RS		-5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs77540055; hg19: chr12-122372183; COSMIC: COSV56614458; COSMIC: COSV56614458;