NM_181861.2:c.*3T>C

Variant names:

• chr12-98732569-T-C
• rs118102803
• NM_181861.2:c.*3T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_181861.2(APAF1):​c.*3T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,542,956 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: APAF1 NM_181861.2 3_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.12
• Publications: 1 publications found

Genes affected

APAF1 (HGNC:576): (apoptotic peptidase activating factor 1) This gene encodes a cytoplasmic protein that initiates apoptosis. This protein contains several copies of the WD-40 domain, a caspase recruitment domain (CARD), and an ATPase domain (NB-ARC). Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves caspase 9 preproprotein, releasing its mature, activated form. Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ANKS1B (HGNC:24600): (ankyrin repeat and sterile alpha motif domain containing 1B) This gene encodes a multi-domain protein that is predominantly expressed in brain and testis. This protein interacts with amyloid beta protein precursor (AbetaPP) and may have a role in normal brain development, and in the pathogenesis of Alzheimer's disease. Expression of this gene has been shown to be elevated in patients with pre-B cell acute lymphocytic leukemia associated with t(1;19) translocation. Alternatively spliced transcript variants encoding different isoforms (some with different subcellular localization, PMID:15004329) have been described for this gene. [provided by RefSeq, Aug 2011]

ANKS1B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 12-98732569-T-C is Benign according to our data. Variant chr12-98732569-T-C is described in ClinVar as Benign. ClinVar VariationId is 3042071.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 407 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181861.2. 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
	APAF1	NM_181861.2	MANE Select	c.*3T>C		3_prime_UTR	Exon 27 of 27	NP_863651.1	O14727-1
	APAF1	NM_013229.3		c.*3T>C		3_prime_UTR	Exon 27 of 27	NP_037361.1	O14727-2
	APAF1	NM_181868.2		c.*3T>C		3_prime_UTR	Exon 26 of 26	NP_863658.1	O14727-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APAF1	ENST00000551964.6	TSL:1 MANE Select	c.*3T>C		3_prime_UTR	Exon 27 of 27	ENSP00000448165.2	O14727-1
	APAF1	ENST00000550527.5	TSL:1	c.*3T>C		3_prime_UTR	Exon 26 of 26	ENSP00000448449.1	O14727-2
	APAF1	ENST00000547045.5	TSL:1	c.*3T>C		3_prime_UTR	Exon 25 of 25	ENSP00000449791.1	O14727-4

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 406 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00286 AC: 683 AN: 238648 AF XY: 0.00268

Gnomad AFR exome AF: 0.000527

Gnomad AMR exome AF: 0.00329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00650

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00320 AC: 4444 AN: 1390640 Hom.: 14 Cov.: 26 AF XY: 0.00309 AC XY: 2151 AN XY: 695080

African (AFR) AF: 0.000475 AC: 15 AN: 31584

American (AMR) AF: 0.00352 AC: 155 AN: 44076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25598

East Asian (EAS) AF: 0.00 AC: 0 AN: 39040

South Asian (SAS) AF: 0.000538 AC: 45 AN: 83666

European-Finnish (FIN) AF: 0.00606 AC: 321 AN: 52972

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5654

European-Non Finnish (NFE) AF: 0.00355 AC: 3730 AN: 1050046

Other (OTH) AF: 0.00305 AC: 177 AN: 58004

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00299 AC XY: 223 AN XY: 74484

African (AFR) AF: 0.000794 AC: 33 AN: 41572

American (AMR) AF: 0.00360 AC: 55 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00782 AC: 83 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00329 AC: 224 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00229

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	APAF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.0
DANN	Benign	0.82
PhyloP100		-2.1
Mutation Taster		=100/0	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: rs118102803; hg19: chr12-99126347;