NM_004928.3:c.766G>A

Variant names:

• chr21-44330203-C-T
• rs766177483
• NM_004928.3:c.766G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004928.3(CFAP410):​c.766G>A​(p.Glu256Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,565,182 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CFAP410 NM_004928.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.913
• Publications: 0 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, SD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000241728 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.098065525).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004928.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP410	NM_004928.3	MANE Select	c.766G>A	p.Glu256Lys	missense	Exon 7 of 7	NP_004919.1	O43822-1
	CFAP410	NM_001271441.2		c.1123G>A	p.Glu375Lys	missense	Exon 7 of 7	NP_001258370.1	O43822-4
	CFAP410	NM_001271440.2		c.763G>A	p.Glu255Lys	missense	Exon 7 of 7	NP_001258369.1	O43822-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP410	ENST00000339818.9	TSL:1 MANE Select	c.766G>A	p.Glu256Lys	missense	Exon 7 of 7	ENSP00000344566.4	O43822-1
	CFAP410	ENST00000397956.7	TSL:1	c.1123G>A	p.Glu375Lys	missense	Exon 7 of 7	ENSP00000381047.3	O43822-4
	CFAP410	ENST00000325223.7	TSL:1	c.763G>A	p.Glu255Lys	missense	Exon 7 of 7	ENSP00000317302.7	O43822-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000346 AC: 6 AN: 173242 AF XY: 0.0000423

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000360

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000761

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1412932 Hom.: 0 Cov.: 30 AF XY: 0.0000186 AC XY: 13 AN XY: 699734

African (AFR) AF: 0.00 AC: 0 AN: 32660

American (AMR) AF: 0.0000257 AC: 1 AN: 38862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25358

East Asian (EAS) AF: 0.0000536 AC: 2 AN: 37308

South Asian (SAS) AF: 0.000111 AC: 9 AN: 81234

European-Finnish (FIN) AF: 0.0000238 AC: 1 AN: 42058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4834

European-Non Finnish (NFE) AF: 0.00000366 AC: 4 AN: 1091932

Other (OTH) AF: 0.00 AC: 0 AN: 58686

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000842 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.91
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.075
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.022	D
Polyphen		0.57	P
Vest4		0.29
MutPred		0.31		Gain of ubiquitination at E256 (P = 0.0029)
MVP		0.22
MPC		0.075
ClinPred		0.082	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.13
Mutation Taster		=96/4	polymorphism

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: rs766177483; hg19: chr21-45750086; COSMIC: COSV57395578; COSMIC: COSV57395578;