20-33068891-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001376932.3(BPIFB3):c.1055C>A(p.Ala352Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BPIFB3 NM_001376932.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

Genes affected

BPIFB3 (HGNC:16178): (BPI fold containing family B member 3) Predicted to enable lipid binding activity. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BPIFB3	NM_001376932.3	c.1055C>A	p.Ala352Asp	missense_variant	11/16	ENST00000375494.4
BPIFB3	NM_182658.5	c.1055C>A	p.Ala352Asp	missense_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BPIFB3	ENST00000375494.4	c.1055C>A	p.Ala352Asp	missense_variant	11/16	1	NM_001376932.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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 06, 2021

The c.1067C>A (p.A356D) alteration is located in exon 10 (coding exon 10) of the BPIFB3 gene. This alteration results from a C to A substitution at nucleotide position 1067, causing the alanine (A) at amino acid position 356 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	0.76
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0047	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.86	D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.80		Loss of sheet (P = 0.0315);
MVP		0.45
MPC		0.59
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.93
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs201582304; hg19: chr20-31656697;