Genetic Variant NM_182519.3:c.211C>T (chr20-33083408-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_182519.3(BPIFB4):c.211C>T(p.Pro71Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,603,206 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. P71T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0064 ( 9 hom., cov: 31)

Exomes 𝑓: 0.00065 ( 7 hom. )

Consequence

BPIFB4
NM_182519.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.323

Publications

5 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004229903).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00636 (960/150984) while in subpopulation AFR AF = 0.0218 (891/40954). AF 95% confidence interval is 0.0206. There are 9 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BPIFB4	NM_182519.3 link	c.211C>T	p.Pro71Ser	missense_variant	Exon 5 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.211C>T	p.Pro71Ser	missense_variant	Exon 5 of 18	5	NM_182519.3	ENSP00000364632.3	P59827-1
BPIFB4	ENST00000674031.1 link	c.577C>T	p.Pro193Ser	missense_variant	Exon 2 of 15			ENSP00000501266.1	A0A669KBJ0
BPIFB4	ENST00000445356.1 link	n.106+1776C>T		intron_variant	Intron 3 of 6	2		ENSP00000388423.1	F8WEG9

Frequencies

GnomAD3 genomes

AF:

0.00635

AC:

958

AN:

150876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00350

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000420

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000590

Gnomad OTH

AF:

0.00436

GnomAD2 exomes

AF:

0.00171

AC:

426

AN:

248950

AF XY:

0.00133

show subpopulations

Gnomad AFR exome

AF:

0.0229

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.000659

GnomAD4 exome

AF:

0.000653

AC:

949

AN:

1452222

Hom.:

Cov.:

AF XY:

0.000545

AC XY:

394

AN XY:

722548

show subpopulations

African (AFR)

AF:

0.0231

AC:

768

AN:

33270

American (AMR)

AF:

0.00137

AC:

AN:

44368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.000233

AC:

AN:

85854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53164

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

1104220

Other (OTH)

AF:

0.00140

AC:

AN:

60056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00636

AC:

960

AN:

150984

Hom.:

Cov.:

AF XY:

0.00656

AC XY:

484

AN XY:

73806

show subpopulations

African (AFR)

AF:

0.0218

AC:

891

AN:

40954

American (AMR)

AF:

0.00350

AC:

AN:

15142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.000420

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000591

AC:

AN:

67732

Other (OTH)

AF:

0.00432

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00262

Hom.:

Bravo

AF:

0.00690

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00199

AC:

241

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0061

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.81

PhyloP100

0.32

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.39

REVEL

Benign

0.020

Sift

Benign

0.087

Sift4G

Benign

0.12

Polyphen

0.075

Vest4

0.25

MVP

0.055

MPC

0.064

ClinPred

0.00089

GERP RS

1.8

Varity_R

0.035

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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NM_182519.3:c.211C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over