21-44330229-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004928.3(CFAP410):c.740G>A(p.Arg247His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,585,248 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (6 hom.)
• Consequence: CFAP410 NM_004928.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.152

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023603141).
• BP6: Variant 21-44330229-C-T is Benign according to our data. Variant chr21-44330229-C-T is described in ClinVar as [Benign]. Clinvar id is 716898.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-44330229-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000643 (98/152344) while in subpopulation EAS AF= 0.0152 (79/5188). AF 95% confidence interval is 0.0125. There are 3 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP410	NM_004928.3	c.740G>A	p.Arg247His	missense_variant	7/7	ENST00000339818.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP410	ENST00000339818.9	c.740G>A	p.Arg247His	missense_variant	7/7	1	NM_004928.3	P4
	ENST00000444409.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152226 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00121 AC: 238 AN: 197044 Hom.: 5 AF XY: 0.00111 AC XY: 120 AN XY: 107998

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.000414

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000118

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000320 AC: 459 AN: 1432904 Hom.: 6 Cov.: 30 AF XY: 0.000319 AC XY: 227 AN XY: 710854

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000242

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00764

Gnomad4 SAS exome AF: 0.000700

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000291

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152344 Hom.: 3 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74508

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0152

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000624 Hom.: 1

Bravo AF: 0.000691

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000982 AC: 118

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	8.4
Dann	Benign	0.83
DEOGEN2	Benign	0.0030	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	0.69	N;N;N
REVEL	Benign	0.014
Sift	Benign	0.61	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.076
MVP		0.15
MPC		0.37
ClinPred		0.020	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.021
gMVP		0.029

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: rs185842266; hg19: chr21-45750112;