chr1-10463533-G-C

Variant names:

• chr1-10463533-G-C
• NM_004401.3:c.529C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004401.3(DFFA):​c.529C>G​(p.Gln177Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: DFFA NM_004401.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19933975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DFFA	NM_004401.3	c.529C>G	p.Gln177Glu	missense_variant	Exon 4 of 6	ENST00000377038.8	NP_004392.1
DFFA	NM_213566.2	c.529C>G	p.Gln177Glu	missense_variant	Exon 4 of 5		NP_998731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DFFA	ENST00000377038.8	c.529C>G	p.Gln177Glu	missense_variant	Exon 4 of 6	1	NM_004401.3	ENSP00000366237.3
DFFA	ENST00000377036.2	c.529C>G	p.Gln177Glu	missense_variant	Exon 4 of 5	1		ENSP00000366235.2
DFFA	ENST00000476658.5	n.442-324C>G		intron_variant	Intron 3 of 4	3		ENSP00000468395.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.529C>G (p.Q177E) alteration is located in exon 4 (coding exon 4) of the DFFA gene. This alteration results from a C to G substitution at nucleotide position 529, causing the glutamine (Q) at amino acid position 177 to be replaced by a glutamic acid (E). 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	0.078
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0013
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.9	M;M
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.046
Sift	Benign	0.058	T;D
Sift4G	Benign	0.11	T;T
Polyphen		0.026	B;B
Vest4		0.17
MutPred		0.67		Loss of MoRF binding (P = 0.0679);Loss of MoRF binding (P = 0.0679);
MVP		0.39
MPC		0.29
ClinPred		0.41	T
GERP RS		4.5
Varity_R		0.16
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-10523590;