Genetic Variant SERPINB3:p.Gly351Val (chr18-63655778-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000283752.10(SERPINB3):c.1052G>T(p.Gly351Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINB3
ENST00000283752.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.54

Publications

29 publications found

Variant links:

Genes affected

SERPINB3 (HGNC:10569): (serpin family B member 3) Enables cysteine-type endopeptidase inhibitor activity; protease binding activity; and virus receptor activity. Involved in several processes, including autocrine signaling; paracrine signaling; and regulation of cellular protein metabolic process. Located in cytoplasmic vesicle; extracellular exosome; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SERPINB3 links:

SERPINB11 (HGNC:14221): (serpin family B member 11) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be located in cytoplasm. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SERPINB11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045467436).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000283752.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB3	NM_006919.3	MANE Select	c.1052G>T	p.Gly351Val	missense	Exon 8 of 8	NP_008850.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SERPINB3	ENST00000283752.10	TSL:1 MANE Select	c.1052G>T	p.Gly351Val	missense	Exon 8 of 8	ENSP00000283752.5
SERPINB3	ENST00000332821.8	TSL:1	c.896G>T	p.Gly299Val	missense	Exon 7 of 7	ENSP00000329498.8
SERPINB11	ENST00000489748.5	TSL:2	c.-214C>A		5_prime_UTR	Exon 2 of 7	ENSP00000480275.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727172

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111926

Other (OTH)

AF:

0.00

AC:

AN:

60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

1535

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.0040

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.061

Eigen

Benign

-3.0

Eigen_PC

Benign

-3.0

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.27

M_CAP

Benign

0.0085

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-1.3

PhyloP100

-2.5

PrimateAI

Benign

0.40

PROVEAN

Benign

1.0

REVEL

Benign

0.15

Sift

Benign

0.68

Sift4G

Benign

0.42

Polyphen

0.0

Vest4

0.066

MutPred

0.34

Loss of disorder (P = 0.0364)

MVP

0.22

MPC

0.026

ClinPred

0.041

GERP RS

-6.0

Varity_R

0.15

gMVP

0.25

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over