18-63655815-C-G

Variant names:

• chr18-63655815-C-G
• rs1181629101
• NM_006919.3:c.1015G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006919.3(SERPINB3):​c.1015G>C​(p.Glu339Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SERPINB3 NM_006919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB3	NM_006919.3	c.1015G>C	p.Glu339Gln	missense_variant	Exon 8 of 8	ENST00000283752.10	NP_008850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB3	ENST00000283752.10	c.1015G>C	p.Glu339Gln	missense_variant	Exon 8 of 8	1	NM_006919.3	ENSP00000283752.5
SERPINB3	ENST00000332821.8	c.859G>C	p.Glu287Gln	missense_variant	Exon 7 of 7	1		ENSP00000329498.8
SERPINB11	ENST00000489748	c.-177C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 7	2		ENSP00000480275.1
SERPINB11	ENST00000489748	c.-177C>G		5_prime_UTR_variant	Exon 2 of 7	2		ENSP00000480275.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251062 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000205 AC: 3 AN: 1461726 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727164

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1015G>C (p.E339Q) alteration is located in exon 8 (coding exon 7) of the SERPINB3 gene. This alteration results from a G to C substitution at nucleotide position 1015, causing the glutamic acid (E) at amino acid position 339 to be replaced by a glutamine (Q). 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	0.24
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;T
Sift4G	Uncertain	0.032	D;D
Polyphen		1.0	D;D
Vest4		0.28
MutPred		0.69		Loss of disorder (P = 0.0939);.;
MVP		0.68
MPC		0.15
ClinPred		0.87	D
GERP RS		3.0
Varity_R		0.60
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs1181629101; hg19: chr18-61323049;