6-3129177-G-A

Variant summary

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

The NM_004332.4(BPHL):c.511G>A(p.Glu171Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000829 in 1,448,120 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: BPHL NM_004332.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

Genes affected

BPHL (HGNC:1094): (biphenyl hydrolase like) This gene encodes a member of the serine protease family of hydrolytic enzymes which contain a serine in their active site. The encoded protein may play a role in activation of the antiviral prodrug valacyclovir. Alternatively spliced transcript variants have been described.[provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BPHL	NM_004332.4	c.511G>A	p.Glu171Lys	missense_variant	4/7	ENST00000380379.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BPHL	ENST00000380379.10	c.511G>A	p.Glu171Lys	missense_variant	4/7	1	NM_004332.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000838 AC: 2 AN: 238584 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.0000358

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000829 AC: 12 AN: 1448120 Hom.: 0 Cov.: 31 AF XY: 0.00000695 AC XY: 5 AN XY: 719210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000356

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000815

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

May 25, 2022

The c.511G>A (p.E171K) alteration is located in exon 4 (coding exon 4) of the BPHL gene. This alteration results from a G to A substitution at nucleotide position 511, causing the glutamic acid (E) at amino acid position 171 to be replaced by a lysine (K). 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	-0.036	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	N;N;D;N
REVEL	Uncertain	0.36
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.029	B;B;.;B
Vest4		0.61
MutPred		0.57		.;Gain of methylation at E171 (P = 0.027);.;.;
MVP		0.35
MPC		0.23
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs774197466; hg19: chr6-3129411; COSMIC: COSV66743046;