chr12-121949042-G-A

Position:

• chr12-121949042-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144668.6(CFAP251):​c.1250G>A​(p.Arg417Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0446 in 1,582,920 control chromosomes in the GnomAD database, including 1,898 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (142 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1756 hom.)
• Consequence: CFAP251 NM_144668.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.651

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=0.0012010038).
• BP6: Variant 12-121949042-G-A is Benign according to our data. Variant chr12-121949042-G-A is described in ClinVar as [Benign]. Clinvar id is 403607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0373 (5674/152054) while in subpopulation SAS AF= 0.0544 (262/4812). AF 95% confidence interval is 0.049. There are 142 homozygotes in gnomad4. There are 2706 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 142 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP251	NM_144668.6	c.1250G>A	p.Arg417Gln	missense_variant	8/22	ENST00000288912.9	NP_653269.3
CFAP251	NM_001178003.2	c.1250G>A	p.Arg417Gln	missense_variant	8/18		NP_001171474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP251	ENST00000288912.9	c.1250G>A	p.Arg417Gln	missense_variant	8/22	1	NM_144668.6	ENSP00000288912
CFAP251	ENST00000397454.2	c.1250G>A	p.Arg417Gln	missense_variant	8/18	1		ENSP00000380595	P1
CFAP251	ENST00000543211.5	n.1374G>A		non_coding_transcript_exon_variant	1/5	3
CFAP251	ENST00000546044.1	n.359G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5663 AN: 151936 Hom.: 140 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0923

Gnomad EAS AF: 0.0372

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0451

GnomAD3 exomes AF: 0.0400 AC: 9313 AN: 232652 Hom.: 238 AF XY: 0.0416 AC XY: 5267 AN XY: 126688

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.0827

Gnomad EAS exome AF: 0.0282

Gnomad SAS exome AF: 0.0489

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0465

Gnomad OTH exome AF: 0.0435

GnomAD4 exome AF: 0.0454 AC: 64983 AN: 1430866 Hom.: 1756 Cov.: 27 AF XY: 0.0456 AC XY: 32482 AN XY: 711748

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.0264

Gnomad4 ASJ exome AF: 0.0825

Gnomad4 EAS exome AF: 0.0439

Gnomad4 SAS exome AF: 0.0486

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0470

Gnomad4 OTH exome AF: 0.0458

GnomAD4 genome AF: 0.0373 AC: 5674 AN: 152054 Hom.: 142 Cov.: 32 AF XY: 0.0364 AC XY: 2706 AN XY: 74330

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.0410

Gnomad4 ASJ AF: 0.0923

Gnomad4 EAS AF: 0.0371

Gnomad4 SAS AF: 0.0544

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0498

Alfa AF: 0.0483 Hom.: 334

Bravo AF: 0.0356

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0501 AC: 193

ESP6500AA AF: 0.0119 AC: 43

ESP6500EA AF: 0.0446 AC: 361

ExAC AF: 0.0425 AC: 5135

Asia WGS AF: 0.0670 AC: 234 AN: 3454

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	0.058
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.4
DANN	Benign	0.59
DEOGEN2	Benign	0.0039	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.4	N;N
REVEL	Benign	0.043
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.049
MPC		0.15
ClinPred		0.00050	T
GERP RS		-0.91
Varity_R		0.030
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs78910014; hg19: chr12-122386948;