rs775122866

Variant names:

• chr20-33083378-A-T
• rs775122866
• NM_182519.3:c.181A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_182519.3(BPIFB4):​c.181A>T​(p.Ile61Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,612,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: BPIFB4 NM_182519.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0460
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03289658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BPIFB4	NM_182519.3	c.181A>T	p.Ile61Phe	missense_variant	Exon 5 of 18	ENST00000375483.4	NP_872325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BPIFB4	ENST00000375483.4	c.181A>T	p.Ile61Phe	missense_variant	Exon 5 of 18	5	NM_182519.3	ENSP00000364632.3
BPIFB4	ENST00000674031.1	c.547A>T	p.Ile183Phe	missense_variant	Exon 2 of 15			ENSP00000501266.1
BPIFB4	ENST00000445356.1	n.106+1746A>T		intron_variant	Intron 3 of 6	2		ENSP00000388423.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151654 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 250922 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 AF: 0.0000192 AC: 28 AN: 1461134 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 726832

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111410

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151654 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74080

African (AFR) AF: 0.00 AC: 0 AN: 41214

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181A>T (p.I61F) alteration is located in exon 3 (coding exon 3) of the BPIFB4 gene. This alteration results from a A to T substitution at nucleotide position 181, causing the isoleucine (I) at amino acid position 61 to be replaced by a phenylalanine (F). 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	Benign	0.089
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.046
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.039
Sift	Benign	0.069	T
Sift4G	Benign	0.064	T
Polyphen		0.037	B
Vest4		0.25
MutPred		0.23		Gain of catalytic residue at I61 (P = 0.2349);
MVP		0.014
MPC		0.14
ClinPred		0.025	T
GERP RS		1.9
Varity_R		0.050
gMVP		0.32
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs775122866; hg19: chr20-31671184;