chr1-10472344-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004401.3(DFFA):​c.115C>T​(p.Leu39Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,455,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

DFFA
NM_004401.3 missense

Scores

5
10
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71
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]
PEX14 (HGNC:8856): (peroxisomal biogenesis factor 14) This gene encodes an essential component of the peroxisomal import machinery. The protein is integrated into peroxisome membranes with its C-terminus exposed to the cytosol, and interacts with the cytosolic receptor for proteins containing a PTS1 peroxisomal targeting signal. The protein also functions as a transcriptional corepressor and interacts with a histone deacetylase. A mutation in this gene results in one form of Zellweger syndrome. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DFFANM_004401.3 linkuse as main transcriptc.115C>T p.Leu39Phe missense_variant 1/6 ENST00000377038.8
DFFANM_213566.2 linkuse as main transcriptc.115C>T p.Leu39Phe missense_variant 1/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DFFAENST00000377038.8 linkuse as main transcriptc.115C>T p.Leu39Phe missense_variant 1/61 NM_004401.3 P1O00273-1
DFFAENST00000377036.2 linkuse as main transcriptc.115C>T p.Leu39Phe missense_variant 1/51 O00273-2
PEX14ENST00000472851.1 linkuse as main transcriptn.57G>A non_coding_transcript_exon_variant 1/43
DFFAENST00000476658.5 linkuse as main transcriptc.115C>T p.Leu39Phe missense_variant, NMD_transcript_variant 1/53

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000122
AC:
3
AN:
246234
Hom.:
0
AF XY:
0.00000749
AC XY:
1
AN XY:
133510
show subpopulations
Gnomad AFR exome
AF:
0.0000635
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:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000213
AC:
31
AN:
1455776
Hom.:
0
Cov.:
30
AF XY:
0.0000180
AC XY:
13
AN XY:
723726
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
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:
0.0000262
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000151

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 submitterclinical testingAmbry GeneticsMar 16, 2022The c.115C>T (p.L39F) alteration is located in exon 1 (coding exon 1) of the DFFA gene. This alteration results from a C to T substitution at nucleotide position 115, causing the leucine (L) at amino acid position 39 to be replaced by a phenylalanine (F). 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
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
D;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.81
T;T
M_CAP
Benign
0.048
D
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Pathogenic
2.9
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Uncertain
0.31
Sift
Benign
0.036
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.52
MVP
0.46
MPC
0.94
ClinPred
0.96
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.64
gMVP
0.58

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.

Other links and lift over

dbSNP: rs1394934836; hg19: chr1-10532401; API