6-3137488-C-T

Variant names:

• chr6-3137488-C-T
• rs1762045441
• NM_004332.4:c.659C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004332.4(BPHL):​c.659C>T​(p.Pro220Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P220R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: BPHL NM_004332.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.94
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28586668).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004332.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPHL	NM_004332.4	MANE Select	c.659C>T	p.Pro220Leu	missense	Exon 5 of 7	NP_004323.2	Q86WA6-1
	BPHL	NM_001302777.1		c.608C>T	p.Pro203Leu	missense	Exon 6 of 8	NP_001289706.1	Q49AI2
	BPHL	NR_026648.2		n.1186+66C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPHL	ENST00000380379.10	TSL:1 MANE Select	c.659C>T	p.Pro220Leu	missense	Exon 5 of 7	ENSP00000369739.5	Q86WA6-1
	BPHL	ENST00000380375.4	TSL:1	c.608C>T	p.Pro203Leu	missense	Exon 5 of 7	ENSP00000369734.3	Q86WA6-2
	BPHL	ENST00000424847.6	TSL:1	n.*752C>T		non_coding_transcript_exon	Exon 6 of 8	ENSP00000394072.2	F2Z2Q1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151670 Hom.: 0 Cov.: 31

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151670 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74024

African (AFR) AF: 0.00 AC: 0 AN: 41256

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.058	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.9
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.37
Sift	Benign	0.22	T
Sift4G	Benign	0.35	T
Polyphen		0.094	B
Vest4		0.41
MutPred		0.58		Gain of MoRF binding (P = 0.0529)
MVP		0.74
MPC		0.21
ClinPred		0.95	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.80
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1762045441; hg19: chr6-3137722;