11-43326516-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001142930.2(API5):​c.760C>G​(p.His254Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: API5 NM_001142930.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
API5	NM_001142930.2	c.760C>G	p.His254Asp	missense_variant	Exon 7 of 14	ENST00000531273.6	NP_001136402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
API5	ENST00000531273.6	c.760C>G	p.His254Asp	missense_variant	Exon 7 of 14	2	NM_001142930.2	ENSP00000431391.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.760C>G (p.H254D) alteration is located in exon 7 (coding exon 7) of the API5 gene. This alteration results from a C to G substitution at nucleotide position 760, causing the histidine (H) at amino acid position 254 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	.;T;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;.;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.60	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.97	T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;T
Polyphen		0.91, 0.77, 0.89	.;P;.;P;P
Vest4		0.81
MutPred		0.44		.;Loss of methylation at K251 (P = 0.0476);.;Loss of methylation at K251 (P = 0.0476);Loss of methylation at K251 (P = 0.0476);
MVP		0.85
MPC		1.7
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.48
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-43348066;