Genetic Variant NM_004332.4:c.380C>T (chr6-3129046-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004332.4(BPHL):c.380C>T(p.Ala127Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,614,190 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0074 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 80 hom. )

Consequence

BPHL
NM_004332.4 missense, splice_region

Scores

Splicing: ADA: 0.01152

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.85

Publications

2 publications found

Variant links:

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]

BPHL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069321394).

BP6

Variant 6-3129046-C-T is Benign according to our data. Variant chr6-3129046-C-T is described in ClinVar as Benign. ClinVar VariationId is 709823.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00742 (1130/152312) while in subpopulation SAS AF = 0.0294 (142/4826). AF 95% confidence interval is 0.0255. There are 14 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BPHL	NM_004332.4	MANE Select	c.380C>T	p.Ala127Val	missense splice_region	Exon 4 of 7	NP_004323.2	Q86WA6-1
BPHL	NM_001302777.1		c.329C>T	p.Ala110Val	missense splice_region	Exon 5 of 8	NP_001289706.1	Q49AI2
BPHL	NR_026648.2		n.973C>T		splice_region non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BPHL	ENST00000380379.10	TSL:1 MANE Select	c.380C>T	p.Ala127Val	missense splice_region	Exon 4 of 7	ENSP00000369739.5	Q86WA6-1
BPHL	ENST00000380375.4	TSL:1	c.329C>T	p.Ala110Val	missense splice_region	Exon 4 of 7	ENSP00000369734.3	Q86WA6-2
BPHL	ENST00000424847.6	TSL:1	n.*473C>T		splice_region non_coding_transcript_exon	Exon 5 of 8	ENSP00000394072.2	F2Z2Q1

Frequencies

GnomAD3 genomes

AF:

0.00744

AC:

1133

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00532

AC:

1339

AN:

251476

AF XY:

0.00610

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.000809

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00262

AC:

3835

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00327

AC XY:

2378

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0237

AC:

792

AN:

33476

American (AMR)

AF:

0.000872

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00942

AC:

374

AN:

39700

South Asian (SAS)

AF:

0.0275

AC:

2371

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1112008

Other (OTH)

AF:

0.00351

AC:

212

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

234

468

701

935

1169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00742

AC:

1130

AN:

152312

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0223

AC:

925

AN:

41568

American (AMR)

AF:

0.00216

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00270

AC:

AN:

5192

South Asian (SAS)

AF:

0.0294

AC:

142

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68020

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00261

Hom.:

Bravo

AF:

0.00736

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00613

AC:

744

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.2

PhyloP100

2.9

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.8

REVEL

Benign

0.10

Sift

Benign

0.11

Sift4G

Benign

0.22

Polyphen

0.049

Vest4

0.13

MVP

0.44

MPC

0.20

ClinPred

0.019

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.096

gMVP

0.65

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.13

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over