1-10463569-A-G

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.493T>C(p.Cys165Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,202 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (26 hom.)
• Consequence: DFFA NM_004401.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.656

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=0.002888918).
• BP6: Variant 1-10463569-A-G is Benign according to our data. Variant chr1-10463569-A-G is described in ClinVar as [Benign]. Clinvar id is 777880.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00817 (1245/152332) while in subpopulation AFR AF= 0.0246 (1024/41578). AF 95% confidence interval is 0.0234. There are 17 homozygotes in gnomad4. There are 602 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DFFA	NM_004401.3	c.493T>C	p.Cys165Arg	missense_variant	4/6	ENST00000377038.8
DFFA	NM_213566.2	c.493T>C	p.Cys165Arg	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DFFA	ENST00000377038.8	c.493T>C	p.Cys165Arg	missense_variant	4/6	1	NM_004401.3	P1
DFFA	ENST00000377036.2	c.493T>C	p.Cys165Arg	missense_variant	4/5	1
DFFA	ENST00000476658.5	c.442-360T>C		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1244 AN: 152214 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00317 AC: 796 AN: 251218 Hom.: 9 AF XY: 0.00271 AC XY: 368 AN XY: 135772

Gnomad AFR exome AF: 0.0239

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000925

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00183 AC: 2681 AN: 1461870 Hom.: 26 Cov.: 31 AF XY: 0.00175 AC XY: 1273 AN XY: 727238

Gnomad4 AFR exome AF: 0.0268

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.0214

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000607

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00817 AC: 1245 AN: 152332 Hom.: 17 Cov.: 32 AF XY: 0.00808 AC XY: 602 AN XY: 74490

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00298 Hom.: 10

Bravo AF: 0.00951

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0222 AC: 98

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00324 AC: 393

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00160

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

Mar 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.8
Dann	Benign	0.68
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.73	N;N
REVEL	Benign	0.099
Sift	Benign	0.66	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.64	P;P
Vest4		0.15
MVP		0.44
MPC		0.45
ClinPred		0.020	T
GERP RS		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs78046004; hg19: chr1-10523626; COSMIC: COSV99058017; COSMIC: COSV99058017;