chr1-10461586-C-T

Variant names:

• chr1-10461586-C-T
• rs78256349
• NM_004401.3:c.900G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004401.3(DFFA):​c.900G>A​(p.Thr300Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000864 in 1,614,232 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (3 hom.)
• Consequence: DFFA NM_004401.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.99
• Publications: 1 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-10461586-C-T is Benign according to our data. Variant chr1-10461586-C-T is described in ClinVar as Benign. ClinVar VariationId is 782903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.99 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.900G>A	p.Thr300Thr	synonymous	Exon 6 of 6	NP_004392.1	O00273-1
	DFFA	NM_213566.2		c.*1448G>A		3_prime_UTR	Exon 5 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.900G>A	p.Thr300Thr	synonymous	Exon 6 of 6	ENSP00000366237.3	O00273-1
	DFFA	ENST00000866602.1		c.945G>A	p.Thr315Thr	synonymous	Exon 6 of 6	ENSP00000536661.1
	DFFA	ENST00000866603.1		c.738G>A	p.Thr246Thr	synonymous	Exon 5 of 5	ENSP00000536662.1

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 576 AN: 152228 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00123 AC: 309 AN: 251448 AF XY: 0.00105

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000560 AC: 819 AN: 1461886 Hom.: 3 Cov.: 31 AF XY: 0.000518 AC XY: 377 AN XY: 727242

African (AFR) AF: 0.0119 AC: 398 AN: 33480

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86258

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.000153 AC: 170 AN: 1112004

Other (OTH) AF: 0.00132 AC: 80 AN: 60396

GnomAD4 genome AF: 0.00377 AC: 575 AN: 152346 Hom.: 8 Cov.: 32 AF XY: 0.00365 AC XY: 272 AN XY: 74494

African (AFR) AF: 0.0129 AC: 536 AN: 41584

American (AMR) AF: 0.000719 AC: 11 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68042

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00381 Hom.: 1

Bravo AF: 0.00418

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.5
DANN	Benign	0.87
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	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: rs78256349; hg19: chr1-10521643;