11-43326516-C-A

Variant names:

• chr11-43326516-C-A
• rs765206937
• NM_001142930.2:c.760C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001142930.2(API5):​c.760C>A​(p.His254Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H254D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: API5 NM_001142930.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

API5 (HGNC:594): (apoptosis inhibitor 5) This gene encodes an apoptosis inhibitory protein whose expression prevents apoptosis after growth factor deprivation. This protein suppresses the transcription factor E2F1-induced apoptosis and also interacts with, and negatively regulates Acinus, a nuclear factor involved in apoptotic DNA fragmentation. Its depletion enhances the cytotoxic action of the chemotherapeutic drugs. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142930.2. 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
	API5	NM_001142930.2	MANE Select	c.760C>A	p.His254Asn	missense	Exon 7 of 14	NP_001136402.1	Q9BZZ5-4
	API5	NM_006595.4		c.760C>A	p.His254Asn	missense	Exon 7 of 14	NP_006586.1	Q9BZZ5-2
	API5	NM_001142931.2		c.598C>A	p.His200Asn	missense	Exon 6 of 13	NP_001136403.1	Q9BZZ5-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	API5	ENST00000531273.6	TSL:2 MANE Select	c.760C>A	p.His254Asn	missense	Exon 7 of 14	ENSP00000431391.1	Q9BZZ5-4
	API5	ENST00000378852.7	TSL:1	c.760C>A	p.His254Asn	missense	Exon 7 of 14	ENSP00000368129.3	Q9BZZ5-2
	API5	ENST00000455725.6	TSL:2	c.727C>A	p.His243Asn	missense	Exon 8 of 15	ENSP00000399341.2	Q9BZZ5-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245378 AF XY: 0.00000755

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.90e-7 AC: 1 AN: 1448870 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 720870

African (AFR) AF: 0.00 AC: 0 AN: 33044

American (AMR) AF: 0.00 AC: 0 AN: 43236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 84238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5444

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104238

Other (OTH) AF: 0.00 AC: 0 AN: 59894

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.13
Sift	Benign	0.71	T
Sift4G	Benign	0.47	T
Polyphen		0.81	P
Vest4		0.69
MutPred		0.41		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.73
MPC		1.0
ClinPred		0.46	T
GERP RS		6.0
Varity_R		0.29
gMVP		0.30
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs765206937; hg19: chr11-43348066;