rs1114167892

Positions:

• chr21-44330298-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_004928.3(CFAP410):​c.671T>C​(p.Leu224Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,452,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFAP410 NM_004928.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.33

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-44330298-A-G is Pathogenic according to our data. Variant chr21-44330298-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 428574.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-44330298-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP410	NM_004928.3	c.671T>C	p.Leu224Pro	missense_variant	7/7	ENST00000339818.9	NP_004919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP410	ENST00000339818.9	c.671T>C	p.Leu224Pro	missense_variant	7/7	1	NM_004928.3	ENSP00000344566.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452728 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722478

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Axial spondylometaphyseal dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.35	T
PROVEAN	Benign	-2.3	N;D;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.67
MutPred		0.71		Gain of sheet (P = 0.0125);.;.;
MVP		0.86
MPC		0.45
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.71
gMVP		0.76

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: rs1114167892; hg19: chr21-45750181;