11-102325144-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001165.5(BIRC3):c.635T>G(p.Leu212Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BIRC3 NM_001165.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

BIRC3 (HGNC:591): (baculoviral IAP repeat containing 3) This gene encodes a member of the IAP family of proteins that inhibit apoptosis by binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2, probably by interfering with activation of ICE-like proteases. The encoded protein inhibits apoptosis induced by serum deprivation but does not affect apoptosis resulting from exposure to menadione, a potent inducer of free radicals. It contains 3 baculovirus IAP repeats and a ring finger domain. Transcript variants encoding the same isoform have been identified. [provided by RefSeq, Aug 2011]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIRC3	NM_001165.5	c.635T>G	p.Leu212Trp	missense_variant	2/9	ENST00000263464.9
BIRC3	NM_182962.3	c.635T>G	p.Leu212Trp	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIRC3	ENST00000263464.9	c.635T>G	p.Leu212Trp	missense_variant	2/9	1	NM_001165.5	P1
	ENST00000673690.1	n.96-2372A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.635T>G (p.L212W) alteration is located in exon 1 (coding exon 1) of the BIRC3 gene. This alteration results from a T to G substitution at nucleotide position 635, causing the leucine (L) at amino acid position 212 to be replaced by a tryptophan (W). 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	0.91
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	27
Dann	Benign	0.96
DEOGEN2	Uncertain	0.54	D;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;.
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	4.4	H;H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.63
MutPred		0.73		Gain of methylation at K211 (P = 0.0634);Gain of methylation at K211 (P = 0.0634);Gain of methylation at K211 (P = 0.0634);
MVP		0.63
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.73

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-102195875;