chr21-44330262-T-C

Variant names:

• chr21-44330262-T-C
• rs11552066
• NM_004928.3:c.707A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004928.3(CFAP410):​c.707A>G​(p.Gln236Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,602,162 control chromosomes in the GnomAD database, including 9,802 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q236W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.093 (742 hom., cov: 34)
  • Exomes 𝑓: 0.11 (9060 hom.)
• Consequence: CFAP410 NM_004928.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.07
• Publications: 18 publications found

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]

CFAP410 Gene-Disease associations (from GenCC):

• axial spondylometaphyseal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000241728 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013685822).
• BP6: Variant 21-44330262-T-C is Benign according to our data. Variant chr21-44330262-T-C is described in ClinVar as Benign. ClinVar VariationId is 259589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP410	NM_004928.3	c.707A>G	p.Gln236Arg	missense_variant	Exon 7 of 7	ENST00000339818.9	NP_004919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP410	ENST00000339818.9	c.707A>G	p.Gln236Arg	missense_variant	Exon 7 of 7	1	NM_004928.3	ENSP00000344566.4

Frequencies

GnomAD3 genomes AF: 0.0934 AC: 14212 AN: 152212 Hom.: 743 Cov.: 34

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.0246

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.105 AC: 23288 AN: 220876 AF XY: 0.107

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.0839

Gnomad EAS exome AF: 0.0238

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.109 AC: 158192 AN: 1449832 Hom.: 9060 Cov.: 31 AF XY: 0.109 AC XY: 78808 AN XY: 720382

African (AFR) AF: 0.0447 AC: 1491 AN: 33356

American (AMR) AF: 0.153 AC: 6657 AN: 43478

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 2234 AN: 25902

East Asian (EAS) AF: 0.0232 AC: 915 AN: 39372

South Asian (SAS) AF: 0.110 AC: 9299 AN: 84684

European-Finnish (FIN) AF: 0.109 AC: 5405 AN: 49400

Middle Eastern (MID) AF: 0.104 AC: 597 AN: 5738

European-Non Finnish (NFE) AF: 0.113 AC: 125491 AN: 1107982

Other (OTH) AF: 0.102 AC: 6103 AN: 59920

GnomAD4 genome AF: 0.0933 AC: 14212 AN: 152330 Hom.: 742 Cov.: 34 AF XY: 0.0936 AC XY: 6974 AN XY: 74492

African (AFR) AF: 0.0504 AC: 2097 AN: 41576

American (AMR) AF: 0.134 AC: 2058 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 315 AN: 3470

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5188

South Asian (SAS) AF: 0.113 AC: 545 AN: 4832

European-Finnish (FIN) AF: 0.113 AC: 1196 AN: 10622

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7583 AN: 68020

Other (OTH) AF: 0.111 AC: 235 AN: 2112

Alfa AF: 0.110 Hom.: 414

Bravo AF: 0.0927

TwinsUK AF: 0.107 AC: 397

ALSPAC AF: 0.118 AC: 456

ESP6500AA AF: 0.0440 AC: 192

ESP6500EA AF: 0.110 AC: 939

ExAC AF: 0.0967 AC: 11627

Asia WGS AF: 0.0780 AC: 269 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 30, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.1
DANN	Benign	0.87
DEOGEN2	Benign	0.012	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.64	T;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		3.1
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.089
MPC		0.18
ClinPred		0.0037	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11552066; hg19: chr21-45750145; COSMIC: COSV57394551; COSMIC: COSV57394551;