chr21-44330206-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_004928.3(CFAP410):​c.763G>A​(p.Ala255Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,568,058 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

CFAP410
NM_004928.3 missense

Scores

17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -1.20
Variant links:
Genes affected
CFAP410 (HGNC:1260): (cilia and flagella associated protein 410) Four alternatively spliced transcript variants encoding four different isoforms have been found for this nuclear gene. All isoforms contain leucine-rich repeats. Three of these isoforms are mitochondrial proteins and one of them lacks the target peptide, so is not located in mitochondrion. This gene is down-regulated in Down syndrome (DS) brain, which may represent mitochondrial dysfunction in DS patients. [provided by RefSeq, Sep 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1
In a chain Cilia- and flagella-associated protein 410 (size 255) in uniprot entity CF410_HUMAN there are 22 pathogenic changes around while only 9 benign (71%) in NM_004928.3
BP4
Computational evidence support a benign effect (MetaRNN=0.005149126).
BP6
Variant 21-44330206-C-T is Benign according to our data. Variant chr21-44330206-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 546908.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr21-44330206-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000663 (101/152368) while in subpopulation NFE AF= 0.00113 (77/68040). AF 95% confidence interval is 0.000928. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFAP410NM_004928.3 linkc.763G>A p.Ala255Thr missense_variant Exon 7 of 7 ENST00000339818.9 NP_004919.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFAP410ENST00000339818.9 linkc.763G>A p.Ala255Thr missense_variant Exon 7 of 7 1 NM_004928.3 ENSP00000344566.4 O43822-1

Frequencies

GnomAD3 genomes
AF:
0.000663
AC:
101
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000506
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00113
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000641
AC:
113
AN:
176270
Hom.:
1
AF XY:
0.000603
AC XY:
58
AN XY:
96124
show subpopulations
Gnomad AFR exome
AF:
0.00105
Gnomad AMR exome
AF:
0.000142
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000873
Gnomad NFE exome
AF:
0.00128
Gnomad OTH exome
AF:
0.000419
GnomAD4 exome
AF:
0.00143
AC:
2030
AN:
1415690
Hom.:
3
Cov.:
30
AF XY:
0.00139
AC XY:
975
AN XY:
701162
show subpopulations
Gnomad4 AFR exome
AF:
0.000275
Gnomad4 AMR exome
AF:
0.000255
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000936
Gnomad4 NFE exome
AF:
0.00178
Gnomad4 OTH exome
AF:
0.00107
GnomAD4 genome
AF:
0.000663
AC:
101
AN:
152368
Hom.:
0
Cov.:
33
AF XY:
0.000604
AC XY:
45
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.000505
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00113
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00119
Hom.:
0
Bravo
AF:
0.000786
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.000921
AC:
4
ESP6500EA
AF:
0.00164
AC:
14
ExAC
AF:
0.000454
AC:
54

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2025- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2017- -
CFAP410-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 05, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.68
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
0.090
DANN
Benign
0.97
DEOGEN2
Benign
0.0059
T;.;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.053
N
LIST_S2
Benign
0.54
T;T;T
M_CAP
Benign
0.0077
T
MetaRNN
Benign
0.0051
T;T;T
MetaSVM
Benign
-1.0
T
PROVEAN
Benign
-0.19
N;N;N
REVEL
Benign
0.0070
Sift
Benign
0.76
T;T;T
Sift4G
Benign
0.36
T;T;T
Polyphen
0.0020
B;.;.
Vest4
0.056
MVP
0.14
MPC
0.32
ClinPred
0.018
T
GERP RS
-6.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.025
gMVP
0.057

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

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

Other links and lift over

dbSNP: rs141195315; hg19: chr21-45750089; COSMIC: COSV99045876; COSMIC: COSV99045876; API