20-33225133-A-T

Position:

• chr20-33225133-A-T

Variant summary

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

The NM_178466.5(BPIFA3):​c.422A>T​(p.His141Leu) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BPIFA3 NM_178466.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.667

Genes affected

BPIFA3 (HGNC:16204): (BPI fold containing family A member 3) Predicted to enable lipid binding activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

BPIFA3 (HGNC:):

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=0.18742928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPIFA3	NM_178466.5	c.422A>T	p.His141Leu	missense_variant	4/7	ENST00000375454.8	NP_848561.2
BPIFA3	NM_001042439.2	c.314A>T	p.His105Leu	missense_variant	3/6		NP_001035904.1
BPIFA3	XR_244132.4	n.649A>T		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BPIFA3	ENST00000375454.8	c.422A>T	p.His141Leu	missense_variant	4/7	5	NM_178466.5	ENSP00000364603.3
BPIFA3	ENST00000375452.3	c.314A>T	p.His105Leu	missense_variant	3/6	1		ENSP00000364601.3
BPIFA3	ENST00000490499.5	n.801A>T		non_coding_transcript_exon_variant	5/7	1
BPIFA3	ENST00000471233.1	n.632A>T		non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Apr 06, 2024

The c.422A>T (p.H141L) alteration is located in exon 4 (coding exon 4) of the BPIFA3 gene. This alteration results from a A to T substitution at nucleotide position 422, causing the histidine (H) at amino acid position 141 to be replaced by a leucine (L). 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	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.38
DANN	Benign	0.68
DEOGEN2	Benign	0.0047	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.031
Sift	Benign	0.14	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.33	B;B
Vest4		0.31
MutPred		0.33		Loss of catalytic residue at H141 (P = 0.0036);.;
MVP		0.085
MPC		0.039
ClinPred		0.23	T
GERP RS		-5.2
Varity_R		0.078
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs756862181; hg19: chr20-31812939;