22-32417148-C-T

Position:

• chr22-32417148-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_174932.3(BPIFC):​c.1261G>A​(p.Val421Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BPIFC NM_174932.3 missense, splice_region
• Scores: Splicing: ADA: 0.8206
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.204

Genes affected

BPIFC (HGNC:16503): (BPI fold containing family C) Predicted to enable lipid binding activity. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35431927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPIFC	NM_174932.3	c.1261G>A	p.Val421Ile	missense_variant, splice_region_variant	15/17	ENST00000300399.9	NP_777592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BPIFC	ENST00000300399.9	c.1261G>A	p.Val421Ile	missense_variant, splice_region_variant	15/17	1	NM_174932.3	ENSP00000300399.3
BPIFC	ENST00000397452.5	c.1261G>A	p.Val421Ile	missense_variant, splice_region_variant	14/16	5		ENSP00000380594.1
BPIFC	ENST00000534972.4	n.*795G>A		splice_region_variant, non_coding_transcript_exon_variant	13/15	5		ENSP00000439123.3
BPIFC	ENST00000534972.4	n.*795G>A		3_prime_UTR_variant	13/15	5		ENSP00000439123.3

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

Sep 04, 2024

The c.1261G>A (p.V421I) alteration is located in exon 13 (coding exon 13) of the BPIFC gene. This alteration results from a G to A substitution at nucleotide position 1261, causing the valine (V) at amino acid position 421 to be replaced by an isoleucine (I). 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	0.098
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0014	T;.;T
Eigen	Benign	0.039
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.61	T;T;.
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.62	N;.;N
REVEL	Benign	0.12
Sift	Benign	0.14	T;.;T
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.63	P;.;P
Vest4		0.16
MutPred		0.77		Loss of methylation at R416 (P = 0.1226);.;Loss of methylation at R416 (P = 0.1226);
MVP		0.27
MPC		0.30
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.072
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.45
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: chr22-32813135;