chr1-10463569-A-G

Position:

chr1-10463569-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004401.3(DFFA):c.493T>C(p.Cys165Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,202 control chromosomes in the GnomAD database, including 43 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 0.0082 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 26 hom. )

Consequence

DFFA
NM_004401.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.656

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002888918).

BP6

Variant 1-10463569-A-G is Benign according to our data. Variant chr1-10463569-A-G is described in ClinVar as [Benign]. Clinvar id is 777880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00817 (1245/152332) while in subpopulation AFR AF= 0.0246 (1024/41578). AF 95% confidence interval is 0.0234. There are 17 homozygotes in gnomad4. There are 602 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DFFA	NM_004401.3 link	c.493T>C	p.Cys165Arg	missense_variant	4/6	ENST00000377038.8	NP_004392.1	O00273-1
DFFA	NM_213566.2 link	c.493T>C	p.Cys165Arg	missense_variant	4/5		NP_998731.1	O00273-2A0A024R4H5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DFFA	ENST00000377038.8 link	c.493T>C	p.Cys165Arg	missense_variant	4/6	1	NM_004401.3	ENSP00000366237.3	O00273-1
DFFA	ENST00000377036.2 link	c.493T>C	p.Cys165Arg	missense_variant	4/5	1		ENSP00000366235.2	O00273-2
DFFA	ENST00000476658.5 link	n.442-360T>C		intron_variant		3		ENSP00000468395.1	K7ERT1

Frequencies

GnomAD3 genomes

AF:

0.00817

AC:

1244

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00317

AC:

796

AN:

251218

Hom.:

AF XY:

0.00271

AC XY:

368

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.0239

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000925

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00183

AC:

2681

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1273

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0268

Gnomad4 AMR exome

AF:

0.00230

Gnomad4 ASJ exome

AF:

0.0214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000487

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000607

Gnomad4 OTH exome

AF:

0.00477

GnomAD4 genome

AF:

0.00817

AC:

1245

AN:

152332

Hom.:

Cov.:

AF XY:

0.00808

AC XY:

602

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0246

Gnomad4 AMR

AF:

0.00497

Gnomad4 ASJ

AF:

0.0222

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00298

Hom.:

Bravo

AF:

0.00951

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0222

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00324

AC:

393

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 02, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.8

DANN

Benign

0.68

DEOGEN2

Benign

0.033

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Benign

0.32

PROVEAN

Benign

0.73

N;N

REVEL

Benign

0.099

Sift

Benign

0.66

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.64

P;P

Vest4

0.15

MVP

0.44

MPC

0.45

ClinPred

0.020

GERP RS

-0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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