Genetic Variant NM_182519.3:c.61G>C (chr20-33081587-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_182519.3(BPIFB4):c.61G>C(p.Glu21Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. E21K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

BPIFB4
NM_182519.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.07

Publications

0 publications found

Variant links:

Genes affected

BPIFB4 (HGNC:16179): (BPI fold containing family B member 4) Predicted to enable lipid binding activity. Predicted to be located in cytoplasm and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

BPIFB4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049658954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BPIFB4	NM_182519.3 link	c.61G>C	p.Glu21Gln	missense_variant	Exon 3 of 18	ENST00000375483.4	NP_872325.2	P59827-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BPIFB4	ENST00000375483.4 link	c.61G>C	p.Glu21Gln	missense_variant	Exon 3 of 18	5	NM_182519.3	ENSP00000364632.3	P59827-1
BPIFB4	ENST00000674031.1 link	c.61G>C	p.Glu21Gln	missense_variant	Exon 1 of 15			ENSP00000501266.1	A0A669KBJ0
BPIFB4	ENST00000445356.1 link	n.61G>C		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000388423.1	F8WEG9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399366

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690182

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078970

Other (OTH)

AF:

0.00

AC:

AN:

58002

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

8.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0032

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.46

M_CAP

Benign

0.0032

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

PhyloP100

1.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.070

REVEL

Benign

0.012

Sift

Benign

0.17

Sift4G

Benign

0.28

Polyphen

0.0030

Vest4

0.099

MutPred

0.29

Gain of MoRF binding (P = 0.0706);

MVP

0.014

MPC

0.056

ClinPred

0.064

GERP RS

1.1

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.042

gMVP

0.13

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over