1-10461512-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004401.3(DFFA):c.974G>A(p.Arg325Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,002 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (34 hom.)
• Consequence: DFFA NM_004401.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.32

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036945045).
• BP6: Variant 1-10461512-C-T is Benign according to our data. Variant chr1-10461512-C-T is described in ClinVar as [Benign]. Clinvar id is 786715.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00167 (254/152280) while in subpopulation EAS AF= 0.032 (166/5180). AF 95% confidence interval is 0.0281. There are 10 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DFFA	NM_004401.3	c.974G>A	p.Arg325Gln	missense_variant	6/6	ENST00000377038.8
DFFA	NM_213566.2	c.*1522G>A		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DFFA	ENST00000377038.8	c.974G>A	p.Arg325Gln	missense_variant	6/6	1	NM_004401.3	P1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152162 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0324

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00270 AC: 679 AN: 251104 Hom.: 8 AF XY: 0.00246 AC XY: 334 AN XY: 135724

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0305

Gnomad SAS exome AF: 0.000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000881

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00145 AC: 2114 AN: 1461722 Hom.: 34 Cov.: 31 AF XY: 0.00150 AC XY: 1089 AN XY: 727148

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0426

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152280 Hom.: 10 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74460

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0320

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.00180

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00265 AC: 322

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.21	B
Vest4		0.096
MVP		0.27
MPC		0.40
ClinPred		0.079	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.20

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: rs140269107; hg19: chr1-10521569; COSMIC: COSV100986620; COSMIC: COSV100986620;