NM_004401.3:c.476A>C

Variant names:

• chr1-10463586-T-G
• rs201908330
• NM_004401.3:c.476A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004401.3(DFFA):​c.476A>C​(p.Gln159Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,614,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: DFFA NM_004401.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.599
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014814317).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004401.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DFFA	NM_004401.3	MANE Select	c.476A>C	p.Gln159Pro	missense	Exon 4 of 6	NP_004392.1	O00273-1
	DFFA	NM_213566.2		c.476A>C	p.Gln159Pro	missense	Exon 4 of 5	NP_998731.1	O00273-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DFFA	ENST00000377038.8	TSL:1 MANE Select	c.476A>C	p.Gln159Pro	missense	Exon 4 of 6	ENSP00000366237.3	O00273-1
	DFFA	ENST00000377036.2	TSL:1	c.476A>C	p.Gln159Pro	missense	Exon 4 of 5	ENSP00000366235.2	O00273-2
	DFFA	ENST00000866602.1		c.521A>C	p.Gln174Pro	missense	Exon 4 of 6	ENSP00000536661.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 251008 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000134 AC: 196 AN: 1461832 Hom.: 1 Cov.: 31 AF XY: 0.000129 AC XY: 94 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111992

Other (OTH) AF: 0.000513 AC: 31 AN: 60394

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000495 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.0
DANN	Benign	0.57
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.60
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Sift4G	Benign	0.24	T
Polyphen		0.92	P
Vest4		0.40
MutPred		0.56		Gain of catalytic residue at Q159 (P = 0.0642)
MVP		0.24
MPC		0.80
ClinPred		0.055	T
GERP RS		-0.55
Varity_R		0.16
gMVP		0.36
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs201908330; hg19: chr1-10523643;