1-10463093-C-G

Position:

chr1-10463093-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004401.3(DFFA):c.748G>C(p.Ala250Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DFFA
NM_004401.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37971604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DFFA	NM_004401.3 linkuse as main transcript	c.748G>C	p.Ala250Pro	missense_variant	5/6	ENST00000377038.8
DFFA	NM_213566.2 linkuse as main transcript	c.748G>C	p.Ala250Pro	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DFFA	ENST00000377038.8 linkuse as main transcript	c.748G>C	p.Ala250Pro	missense_variant	5/6	1	NM_004401.3	P1	O00273-1
DFFA	ENST00000377036.2 linkuse as main transcript	c.748G>C	p.Ala250Pro	missense_variant	5/5	1			O00273-2
DFFA	ENST00000476658.5 linkuse as main transcript	c.*78G>C		3_prime_UTR_variant, NMD_transcript_variant	4/5	3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251464

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000145

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.000215

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.748G>C (p.A250P) alteration is located in exon 5 (coding exon 5) of the DFFA gene. This alteration results from a G to C substitution at nucleotide position 748, causing the alanine (A) at amino acid position 250 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.040

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.38

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.028

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.99

D;D

Vest4

0.72

MVP

0.44

MPC

0.97

ClinPred

0.35

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.27

gMVP

0.31

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

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