1-10472344-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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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]

ACMG classification

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
DFFA	NM_004401.3	c.115C>T	p.Leu39Phe	missense_variant	1/6	ENST00000377038.8
DFFA	NM_213566.2	c.115C>T	p.Leu39Phe	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DFFA	ENST00000377038.8	c.115C>T	p.Leu39Phe	missense_variant	1/6	1	NM_004401.3	P1
DFFA	ENST00000377036.2	c.115C>T	p.Leu39Phe	missense_variant	1/5	1
PEX14	ENST00000472851.1	n.57G>A		non_coding_transcript_exon_variant	1/4	3
DFFA	ENST00000476658.5	c.115C>T	p.Leu39Phe	missense_variant, NMD_transcript_variant	1/5	3

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

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

The 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

Other links and lift over

dbSNP: rs1394934836; hg19: chr1-10532401;