Genetic Variant CFAP46:p.Ala2578Thr (chr10-132808837-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001200049.3(CFAP46):c.7732G>A(p.Ala2578Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000022 in 1,453,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CFAP46
NM_001200049.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.191

Publications

1 publications found

Variant links:

Genes affected

CFAP46 (HGNC:25247): (cilia and flagella associated protein 46) Predicted to be involved in axoneme assembly. Predicted to be located in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

CFAP46 links:

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ACMG classification

Classification was made for transcript

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=0.040947765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP46	NM_001200049.3 link	c.7732G>A	p.Ala2578Thr	missense_variant	Exon 58 of 58	ENST00000368586.10	NP_001186978.2	Q8IYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP46	ENST00000368586.10 link	c.7732G>A	p.Ala2578Thr	missense_variant	Exon 58 of 58	5	NM_001200049.3	ENSP00000357575.4		Q8IYW2-1
CFAP46	ENST00000639072.2 link	c.7869G>A	p.Thr2623Thr	synonymous_variant	Exon 59 of 59	5		ENSP00000491877.2		A0A1W2PQB9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000168

AC:

AN:

237482

AF XY:

0.0000310

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000192

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1453346

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

721314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

44340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39438

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000253

AC:

AN:

1106496

Other (OTH)

AF:

0.0000334

AC:

AN:

59926

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2668G>A (p.A890T) alteration is located in exon 23 (coding exon 23) of the CFAP46 gene. This alteration results from a G to A substitution at nucleotide position 2668, causing the alanine (A) at amino acid position 890 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.6

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0059

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.33

M_CAP

Benign

0.014

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.97

PhyloP100

-0.19

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.19

REVEL

Benign

0.018

Sift

Benign

0.31

Sift4G

Benign

0.23

Vest4

0.030

MVP

0.014

MPC

0.11

ClinPred

0.031

GERP RS

-1.3

Varity_R

0.040

gMVP

0.032

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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chr10-132808837-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over