chr1-3865989-C-T

Position:

• chr1-3865989-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004402.4(DFFB):​c.419C>T​(p.Pro140Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,567,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: DFFB NM_004402.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

Genes affected

DFFB (HGNC:2773): (DNA fragmentation factor subunit beta) 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. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene but the biological validity of some of these variants has not been determined. [provided by RefSeq, Sep 2013]

DFFB (HGNC:):

ACMG classification

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=0.35617852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DFFB	NM_004402.4	c.419C>T	p.Pro140Leu	missense_variant	3/7	ENST00000378209.8	NP_004393.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DFFB	ENST00000378209.8	c.419C>T	p.Pro140Leu	missense_variant	3/7	1	NM_004402.4	ENSP00000367454.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000143 AC: 3 AN: 209518 Hom.: 0 AF XY: 0.0000177 AC XY: 2 AN XY: 112904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000572

Gnomad SAS exome AF: 0.0000440

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 18 AN: 1415422 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 10 AN XY: 697736

Gnomad4 AFR exome AF: 0.0000922

Gnomad4 AMR exome AF: 0.0000484

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000921

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152010 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74250

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ExAC AF: 0.0000166 AC: 2

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

Sep 03, 2024

The c.419C>T (p.P140L) alteration is located in exon 3 (coding exon 3) of the DFFB gene. This alteration results from a C to T substitution at nucleotide position 419, causing the proline (P) at amino acid position 140 to be replaced by a leucine (L). 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	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	.;D
REVEL	Benign	0.042
Sift	Benign	0.31	.;T
Sift4G	Benign	0.13	T;T
Polyphen		0.96	D;P
Vest4		0.25
MutPred		0.46		.;Loss of catalytic residue at P139 (P = 0.0121);
MVP		0.37
MPC		0.25
ClinPred		0.30	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.070
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

Other links and lift over

dbSNP: rs773522402; hg19: chr1-3782553;