17-78215982-G-C

Variant names:

• chr17-78215982-G-C
• rs777906759
• ENST00000301633.8:c.238G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012271.2(BIRC5):​c.238G>C​(p.Ala80Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A80T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BIRC5 NM_001012271.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.693
• Publications: 1 publications found

Genes affected

BIRC5 (HGNC:593): (baculoviral IAP repeat containing 5) This gene is a member of the inhibitor of apoptosis (IAP) gene family, which encode negative regulatory proteins that prevent apoptotic cell death. IAP family members usually contain multiple baculovirus IAP repeat (BIR) domains, but this gene encodes proteins with only a single BIR domain. The encoded proteins also lack a C-terminus RING finger domain. Gene expression is high during fetal development and in most tumors, yet low in adult tissues. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07538757).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012271.2. 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
	BIRC5	NM_001168.3	MANE Select	c.222-682G>C		intron	N/A	NP_001159.2	A0A0B4J1S3
	BIRC5	NM_001012271.2		c.238G>C	p.Ala80Pro	missense	Exon 3 of 5	NP_001012271.1	H3BLT4
	BIRC5	NM_001012270.2		c.221+1193G>C		intron	N/A	NP_001012270.1	O15392-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BIRC5	ENST00000301633.8	TSL:1	c.238G>C	p.Ala80Pro	missense	Exon 3 of 5	ENSP00000301633.3	H3BLT4
	BIRC5	ENST00000587746.5	TSL:1	c.169G>C	p.Ala57Pro	missense	Exon 3 of 5	ENSP00000466675.1	K7EMW2
	BIRC5	ENST00000350051.8	TSL:1 MANE Select	c.222-682G>C		intron	N/A	ENSP00000324180.4	A0A0B4J1S3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000775 AC: 9 AN: 116092 AF XY: 0.0000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000889

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000878 AC: 8 AN: 911670 Hom.: 0 Cov.: 29 AF XY: 0.00000233 AC XY: 1 AN XY: 429630

African (AFR) AF: 0.00 AC: 0 AN: 17722

American (AMR) AF: 0.000798 AC: 8 AN: 10030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6126

East Asian (EAS) AF: 0.00 AC: 0 AN: 7620

South Asian (SAS) AF: 0.00 AC: 0 AN: 23712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 795730

Other (OTH) AF: 0.00 AC: 0 AN: 29900

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000859 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.4
DANN	Benign	0.54
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.69
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.13
Sift	Benign	0.26	T
Sift4G	Benign	0.26	T
Vest4		0.12
MutPred		0.73		Loss of catalytic residue at A80 (P = 0.0121)
MVP		0.39
MPC		0.42
ClinPred		0.078	T
GERP RS		0.35
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs777906759; hg19: chr17-76212063;