Genetic Variant NM_004928.3:c.172G>T (chr21-44333234-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004928.3(CFAP410):c.172G>T(p.Val58Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00998 in 1,612,464 control chromosomes in the GnomAD database, including 105 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 (★★).

Frequency

Genomes: 𝑓 0.0088 ( 16 hom., cov: 34)

Exomes 𝑓: 0.010 ( 89 hom. )

Consequence

CFAP410
NM_004928.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.292

Publications

19 publications found

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]

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

CFAP410 links:

ENSG00000184441 (HGNC:):

ENSG00000184441 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0025855005).

BP6

Variant 21-44333234-C-A is Benign according to our data. Variant chr21-44333234-C-A is described in ClinVar as Benign. ClinVar VariationId is 259585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00882 (1344/152380) while in subpopulation AMR AF = 0.0119 (182/15314). AF 95% confidence interval is 0.0112. There are 16 homozygotes in GnomAd4. There are 712 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFAP410	NM_004928.3	MANE Select	c.172G>T	p.Val58Leu	missense	Exon 4 of 7	NP_004919.1
CFAP410	NM_001271441.2		c.172G>T	p.Val58Leu	missense	Exon 4 of 7	NP_001258370.1
CFAP410	NM_001271440.2		c.172G>T	p.Val58Leu	missense	Exon 4 of 7	NP_001258369.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CFAP410	ENST00000339818.9	TSL:1 MANE Select	c.172G>T	p.Val58Leu	missense	Exon 4 of 7	ENSP00000344566.4
CFAP410	ENST00000397956.7	TSL:1	c.172G>T	p.Val58Leu	missense	Exon 4 of 7	ENSP00000381047.3
CFAP410	ENST00000325223.7	TSL:1	c.172G>T	p.Val58Leu	missense	Exon 4 of 7	ENSP00000317302.7

Frequencies

GnomAD3 genomes

AF:

0.00882

AC:

1343

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0119

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00798

AC:

1933

AN:

242326

AF XY:

0.00811

show subpopulations

Gnomad AFR exome

AF:

0.00128

Gnomad AMR exome

AF:

0.00516

Gnomad ASJ exome

AF:

0.000407

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0109

Gnomad OTH exome

AF:

0.00774

GnomAD4 exome

AF:

0.0101

AC:

14747

AN:

1460084

Hom.:

Cov.:

AF XY:

0.00983

AC XY:

7141

AN XY:

726240

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33466

American (AMR)

AF:

0.00484

AC:

216

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000964

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.0216

AC:

1127

AN:

52196

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0115

AC:

12771

AN:

1111718

Other (OTH)

AF:

0.00795

AC:

480

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

788

1576

2365

3153

3941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

474

948

1422

1896

2370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00882

AC:

1344

AN:

152380

Hom.:

Cov.:

AF XY:

0.00956

AC XY:

712

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41592

American (AMR)

AF:

0.0119

AC:

182

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00228

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0236

AC:

251

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

808

AN:

68034

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00960

Hom.:

Bravo

AF:

0.00673

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00731

AC:

887

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0106

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0064

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.92

PhyloP100

-0.29

PROVEAN

Benign

-0.22

REVEL

Benign

0.023

Sift

Benign

0.48

Sift4G

Benign

1.0

Polyphen

0.015

Vest4

0.26

MutPred

0.46

Gain of disorder (P = 0.1069)

MVP

0.061

MPC

0.25

ClinPred

0.0084

GERP RS

-0.56

Varity_R

0.041

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over