10-104140843-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_025145.7(CFAP43):c.4430G>A(p.Arg1477Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,590,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1477W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CFAP43 NM_025145.7 missense, splice_region
• Scores: Splicing: ADA: 0.9420
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.10

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 Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008380413).
• BP6: Variant 10-104140843-C-T is Benign according to our data. Variant chr10-104140843-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 725604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00202 (307/152208) while in subpopulation AFR AF= 0.00703 (292/41536). AF 95% confidence interval is 0.00637. There are 0 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP43	NM_025145.7	c.4430G>A	p.Arg1477Gln	missense_variant, splice_region_variant	34/38	ENST00000357060.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP43	ENST00000357060.8	c.4430G>A	p.Arg1477Gln	missense_variant, splice_region_variant	34/38	1	NM_025145.7	P1
CFAP43	ENST00000434629.5	c.2426G>A	p.Arg809Gln	missense_variant, splice_region_variant	19/23	1
CFAP43	ENST00000457071.5	c.977G>A	p.Arg326Gln	missense_variant, splice_region_variant	8/12	2
CFAP43	ENST00000479392.1	n.194G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00705

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

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: 0.0000441

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000659 AC: 152 AN: 230774 Hom.: 0 AF XY: 0.000512 AC XY: 64 AN XY: 124884

Gnomad AFR exome AF: 0.00810

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.000210 AC: 302 AN: 1437988 Hom.: 0 Cov.: 29 AF XY: 0.000186 AC XY: 133 AN XY: 715010

Gnomad4 AFR exome AF: 0.00623

Gnomad4 AMR exome AF: 0.000234

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000362

Gnomad4 OTH exome AF: 0.000589

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74414

Gnomad4 AFR AF: 0.00703

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000355 Hom.: 0

Bravo AF: 0.00224

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000741 AC: 90

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CFAP43-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.11
Sift	Uncertain	0.020	D
Sift4G	Benign	0.23	T
Polyphen		0.99	D
Vest4		0.26
MVP		0.42
MPC		0.48
ClinPred		0.054	T
GERP RS		5.5
Varity_R		0.25
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.67
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: rs146971757; hg19: chr10-105900601;