10-104143495-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_025145.7(CFAP43):c.4089A>C(p.Glu1363Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000932 in 1,614,112 control chromosomes in the GnomAD database, including 3 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 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (3 hom.)
• Consequence: CFAP43 NM_025145.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.831

Genes affected

CFAP43 (HGNC:26684): (cilia and flagella associated protein 43) This gene encodes a member of the cilia- and flagella-associated protein family. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045016676).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000434 (66/152236) while in subpopulation NFE AF= 0.000808 (55/68038). AF 95% confidence interval is 0.000638. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP43	NM_025145.7	c.4089A>C	p.Glu1363Asp	missense_variant	32/38	ENST00000357060.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP43	ENST00000357060.8	c.4089A>C	p.Glu1363Asp	missense_variant	32/38	1	NM_025145.7	P1
CFAP43	ENST00000434629.5	c.2085A>C	p.Glu695Asp	missense_variant	17/23	1
CFAP43	ENST00000457071.5	c.636A>C	p.Glu212Asp	missense_variant	6/12	2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

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: 0.000808

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000398 AC: 100 AN: 251366 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135862

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000827

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000984 AC: 1438 AN: 1461876 Hom.: 3 Cov.: 31 AF XY: 0.000965 AC XY: 702 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74382

Gnomad4 AFR AF: 0.000241

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: 0.000808

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000744 Hom.: 6

Bravo AF: 0.000385

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.4089A>C (p.E1363D) alteration is located in exon 32 (coding exon 32) of the CFAP43 gene. This alteration results from a A to C substitution at nucleotide position 4089, causing the glutamic acid (E) at amino acid position 1363 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Benign	0.049
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	0.62	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.014
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.18	B
Vest4		0.10
MutPred		0.21		Loss of helix (P = 0.1299);
MVP		0.23
MPC		0.12
ClinPred		0.023	T
GERP RS		2.0
Varity_R		0.084
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs148991902; hg19: chr10-105903253;