1-10461512-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004401.3(DFFA):c.974G>A(p.Arg325Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,002 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0017 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 34 hom. )

Consequence

DFFA
NM_004401.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.32

Variant links:

Genes affected

DFFA (HGNC:2772): (DNA fragmentation factor subunit alpha) Apoptosis is a cell death process that removes toxic and/or useless cells during mammalian development. The apoptotic process is accompanied by shrinkage and fragmentation of the cells and nuclei and degradation of the chromosomal DNA into nucleosomal units. DNA fragmentation factor (DFF) is a heterodimeric protein of 40-kD (DFFB) and 45-kD (DFFA) subunits. DFFA is the substrate for caspase-3 and triggers DNA fragmentation during apoptosis. DFF becomes activated when DFFA is cleaved by caspase-3. The cleaved fragments of DFFA dissociate from DFFB, the active component of DFF. DFFB has been found to trigger both DNA fragmentation and chromatin condensation during apoptosis. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DFFA links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036945045).

BP6

Variant 1-10461512-C-T is Benign according to our data. Variant chr1-10461512-C-T is described in ClinVar as [Benign]. Clinvar id is 786715.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00167 (254/152280) while in subpopulation EAS AF = 0.032 (166/5180). AF 95% confidence interval is 0.0281. There are 10 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DFFA	NM_004401.3 link	c.974G>A	p.Arg325Gln	missense_variant	Exon 6 of 6	ENST00000377038.8	NP_004392.1	O00273-1
DFFA	NM_213566.2 link	c.*1522G>A		3_prime_UTR_variant	Exon 5 of 5		NP_998731.1	O00273-2A0A024R4H5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DFFA	ENST00000377038.8 link	c.974G>A	p.Arg325Gln	missense_variant	Exon 6 of 6	1	NM_004401.3	ENSP00000366237.3		O00273-1
DFFA	ENST00000476658.5 link	n.*374G>A		downstream_gene_variant		3		ENSP00000468395.1		K7ERT1

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0324

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00270

AC:

679

AN:

251104

AF XY:

0.00246

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0305

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00145

AC:

2114

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

1089

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00139

AC:

AN:

44706

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26124

Gnomad4 EAS exome

AF:

0.0426

AC:

1692

AN:

39688

Gnomad4 SAS exome

AF:

0.00110

AC:

AN:

86226

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53410

Gnomad4 NFE exome

AF:

0.0000549

AC:

AN:

1111930

Gnomad4 Remaining exome

AF:

0.00295

AC:

178

AN:

60390

Heterozygous variant carriers

111

222

333

444

555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00167

AC:

254

AN:

152280

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000770

AC:

0.000769749

AN:

0.000769749

Gnomad4 AMR

AF:

0.00190

AC:

0.00189666

AN:

0.00189666

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.0320

AC:

0.0320463

AN:

0.0320463

Gnomad4 SAS

AF:

0.00186

AC:

0.00186258

AN:

0.00186258

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000882

AC:

0.0000882197

AN:

0.0000882197

Gnomad4 OTH

AF:

0.00567

AC:

0.00567108

AN:

0.00567108

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<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:

0.000169

Hom.:

Bravo

AF:

0.00180

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00265

AC:

322

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

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

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.2

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.21

Vest4

0.096

MVP

0.27

MPC

0.40

ClinPred

0.079

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.20

Mutation Taster

=98/2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over