1-10463076-T-A

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.765A>T(p.Leu255Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,614,120 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: DFFA NM_004401.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.919

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=0.004524857).
• BP6: Variant 1-10463076-T-A is Benign according to our data. Variant chr1-10463076-T-A is described in ClinVar as [Benign]. Clinvar id is 791778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1802/152230) while in subpopulation AFR AF= 0.0406 (1686/41532). AF 95% confidence interval is 0.039. There are 29 homozygotes in gnomad4. There are 851 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DFFA	NM_004401.3	c.765A>T	p.Leu255Phe	missense_variant	5/6	ENST00000377038.8
DFFA	NM_213566.2	c.765A>T	p.Leu255Phe	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DFFA	ENST00000377038.8	c.765A>T	p.Leu255Phe	missense_variant	5/6	1	NM_004401.3	P1
DFFA	ENST00000377036.2	c.765A>T	p.Leu255Phe	missense_variant	5/5	1
DFFA	ENST00000476658.5	c.*95A>T		3_prime_UTR_variant, NMD_transcript_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1796 AN: 152112 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00299 AC: 751 AN: 251474 Hom.: 10 AF XY: 0.00216 AC XY: 294 AN XY: 135914

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00122 AC: 1786 AN: 1461890 Hom.: 34 Cov.: 31 AF XY: 0.00105 AC XY: 763 AN XY: 727246

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0118 AC: 1802 AN: 152230 Hom.: 29 Cov.: 32 AF XY: 0.0114 AC XY: 851 AN XY: 74434

Gnomad4 AFR AF: 0.0406

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00181 Hom.: 2

Bravo AF: 0.0138

ESP6500AA AF: 0.0363 AC: 160

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00358 AC: 434

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

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

Mar 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.084	N
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.47
MutPred		0.78		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.23
MPC		0.95
ClinPred		0.050	T
GERP RS		-6.1
Varity_R		0.40
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: rs35783598; hg19: chr1-10523133;