1-10463076-T-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004401.3(DFFA):c.765A>T(p.Leu255Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,614,120 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 29 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 34 hom. )

Consequence

DFFA
NM_004401.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.919

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004524857).

BP6

Variant 1-10463076-T-A is Benign according to our data. Variant chr1-10463076-T-A is described in ClinVar as [Benign]. Clinvar id is 791778.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1802/152230) while in subpopulation AFR AF= 0.0406 (1686/41532). AF 95% confidence interval is 0.039. There are 29 homozygotes in gnomad4. There are 851 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DFFA	NM_004401.3 link	c.765A>T	p.Leu255Phe	missense_variant	Exon 5 of 6	ENST00000377038.8	NP_004392.1	O00273-1
DFFA	NM_213566.2 link	c.765A>T	p.Leu255Phe	missense_variant	Exon 5 of 5		NP_998731.1	O00273-2A0A024R4H5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DFFA	ENST00000377038.8 link	c.765A>T	p.Leu255Phe	missense_variant	Exon 5 of 6	1	NM_004401.3	ENSP00000366237.3	O00273-1
DFFA	ENST00000377036.2 link	c.765A>T	p.Leu255Phe	missense_variant	Exon 5 of 5	1		ENSP00000366235.2	O00273-2
DFFA	ENST00000476658.5 link	n.*95A>T		non_coding_transcript_exon_variant	Exon 4 of 5	3		ENSP00000468395.1	K7ERT1
DFFA	ENST00000476658.5 link	n.*95A>T		3_prime_UTR_variant	Exon 4 of 5	3		ENSP00000468395.1	K7ERT1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1796

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0406

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00299

AC:

751

AN:

251474

Hom.:

AF XY:

0.00216

AC XY:

294

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.0402

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00122

AC:

1786

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

763

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0423

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.00320

GnomAD4 genome

AF:

0.0118

AC:

1802

AN:

152230

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

851

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0406

Gnomad4 AMR

AF:

0.00556

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00181

Hom.:

Bravo

AF:

0.0138

ESP6500AA

AF:

0.0363

AC:

160

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00358

AC:

434

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000164

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

Mar 02, 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

0.13

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.084

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.47

MutPred

0.78

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.23

MPC

0.95

ClinPred

0.050

GERP RS

-6.1

Varity_R

0.40

gMVP

0.29

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