Genetic Variant CFAP96:p.Glu285Lys (chr4-185445102-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001114357.3(CFAP96):c.853G>A(p.Glu285Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,551,456 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

CFAP96
NM_001114357.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.470

Variant links:

Genes affected

CFAP96 (HGNC:34346): (cilia and flagella associated protein 96) Located in 9+0 non-motile cilium; centrosome; and cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

CFAP96 links:

CCDC110 (HGNC:28504): (coiled-coil domain containing 110) Predicted to be located in nucleus. Predicted to be active in cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

CCDC110 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP96	NM_001114357.3 link	c.853G>A	p.Glu285Lys	missense_variant	Exon 7 of 8	ENST00000378850.5	NP_001107829.1	A7E2U8
CCDC110	NM_152775.4 link	c.*400C>T		downstream_gene_variant		ENST00000307588.8	NP_689988.1	Q8TBZ0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C4orf47	ENST00000378850.5 link	c.853G>A	p.Glu285Lys	missense_variant	Exon 7 of 8	1	NM_001114357.3	ENSP00000368127.4		A7E2U8
CCDC110	ENST00000307588.8 link	c.*400C>T		downstream_gene_variant		1	NM_152775.4	ENSP00000306776.3		Q8TBZ0-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000221

AC:

AN:

153966

Hom.:

AF XY:

0.000233

AC XY:

AN XY:

81694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000486

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000546

AC:

764

AN:

1399298

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

346

AN XY:

690148

show subpopulations

Gnomad4 AFR exome

AF:

0.0000949

Gnomad4 AMR exome

AF:

0.000196

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000675

Gnomad4 OTH exome

AF:

0.000448

GnomAD4 genome

AF:

0.000177

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000134

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.853G>A (p.E285K) alteration is located in exon 6 (coding exon 6) of the C4orf47 gene. This alteration results from a G to A substitution at nucleotide position 853, causing the glutamic acid (E) at amino acid position 285 to be replaced by a lysine (K). 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

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.0

DANN

Benign

0.61

DEOGEN2

Benign

0.00058

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.74

M_CAP

Benign

0.0021

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PROVEAN

Benign

0.30

REVEL

Benign

0.051

Sift

Benign

0.90

Sift4G

Benign

0.93

Polyphen

0.0070

Vest4

0.14

MVP

0.030

ClinPred

0.037

GERP RS

1.1

Varity_R

0.028

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over