chr22-32415932-C-G

Position:

• chr22-32415932-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_174932.3(BPIFC):​c.1384G>C​(p.Asp462His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,438,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: BPIFC NM_174932.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.317

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16904667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPIFC	NM_174932.3	c.1384G>C	p.Asp462His	missense_variant	16/17	ENST00000300399.9	NP_777592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BPIFC	ENST00000300399.9	c.1384G>C	p.Asp462His	missense_variant	16/17	1	NM_174932.3	ENSP00000300399.3
BPIFC	ENST00000397452.5	c.1384G>C	p.Asp462His	missense_variant	15/16	5		ENSP00000380594.1
BPIFC	ENST00000534972.4	n.*918G>C		non_coding_transcript_exon_variant	14/15	5		ENSP00000439123.3
BPIFC	ENST00000534972.4	n.*918G>C		3_prime_UTR_variant	14/15	5		ENSP00000439123.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1438018 Hom.: 0 Cov.: 28 AF XY: 0.00000419 AC XY: 3 AN XY: 715550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000783

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 07, 2024

The c.1384G>C (p.D462H) alteration is located in exon 14 (coding exon 14) of the BPIFC gene. This alteration results from a G to C substitution at nucleotide position 1384, causing the aspartic acid (D) at amino acid position 462 to be replaced by a histidine (H). 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	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0034	T;.;T
Eigen	Benign	0.068
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.80	T;T;.
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.26
Sift	Benign	0.12	T;.;T
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.97	D;.;D
Vest4		0.092
MutPred		0.65		Loss of stability (P = 0.0772);.;Loss of stability (P = 0.0772);
MVP		0.30
MPC		0.37
ClinPred		0.76	D
GERP RS		1.1
Varity_R		0.19
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1211185577; hg19: chr22-32811919; COSMIC: COSV53280874; COSMIC: COSV53280874;