6-3129172-C-G

Variant names:

• chr6-3129172-C-G
• rs749080142
• NM_004332.4:c.506C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004332.4(BPHL):​c.506C>G​(p.Thr169Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,449,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.0000014 (0 hom.)
• Consequence: BPHL NM_004332.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17806834).

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.506C>G	p.Thr169Ser	missense	Exon 4 of 7	NP_004323.2	Q86WA6-1
	BPHL	NM_001302777.1		c.455C>G	p.Thr152Ser	missense	Exon 5 of 8	NP_001289706.1	Q49AI2
	BPHL	NR_026648.2		n.1099C>G		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPHL	ENST00000380379.10	TSL:1 MANE Select	c.506C>G	p.Thr169Ser	missense	Exon 4 of 7	ENSP00000369739.5	Q86WA6-1
	BPHL	ENST00000380375.4	TSL:1	c.455C>G	p.Thr152Ser	missense	Exon 4 of 7	ENSP00000369734.3	Q86WA6-2
	BPHL	ENST00000424847.6	TSL:1	n.*599C>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000394072.2	F2Z2Q1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000831 AC: 2 AN: 240542 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449572 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720132

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33006

American (AMR) AF: 0.0000464 AC: 2 AN: 43064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 84568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105620

Other (OTH) AF: 0.00 AC: 0 AN: 59776

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.24	N
PhyloP100		4.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.16
Sift	Benign	0.26	T
Sift4G	Benign	0.66	T
Polyphen		0.0080	B
Vest4		0.18
MutPred		0.36		Gain of disorder (P = 0.0354)
MVP		0.49
MPC		0.18
ClinPred		0.20	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.69
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749080142; hg19: chr6-3129406;