Variant chr18-63656878-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006919.3(SERPINB3):c.721C>G(p.Leu241Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000636 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

SERPINB3
NM_006919.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.812

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB3	NM_006919.3 linkuse as main transcript	c.721C>G	p.Leu241Val	missense_variant	7/8	ENST00000283752.10	NP_008850.1	P29508-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SERPINB3	ENST00000283752.10 linkuse as main transcript	c.721C>G	p.Leu241Val	missense_variant	7/8	1	NM_006919.3	ENSP00000283752.5	P29508-1
SERPINB3	ENST00000332821.8 linkuse as main transcript	c.612+392C>G		intron_variant		1		ENSP00000329498.8	P29508-2
SERPINB11	ENST00000489748.5 linkuse as main transcript	c.-16+902G>C		intron_variant		2		ENSP00000480275.1	A0A087WWJ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250906

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000636

AC:

AN:

1461192

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726882

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000819

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000548

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2024

The c.721C>G (p.L241V) alteration is located in exon 7 (coding exon 6) of the SERPINB3 gene. This alteration results from a C to G substitution at nucleotide position 721, causing the leucine (L) at amino acid position 241 to be replaced by a valine (V). 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

0.13

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.54

MutPred

0.66

Gain of catalytic residue at M243 (P = 0.0394);

MVP

0.82

MPC

0.19

ClinPred

0.94

GERP RS

2.6

Varity_R

0.88

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over