18-63655778-C-G

Position:

• chr18-63655778-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006919.3(SERPINB3):​c.1052G>C​(p.Gly351Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,601,132 control chromosomes in the GnomAD database, including 20,570 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (1619 hom., cov: 31)
  • Exomes 𝑓: 0.16 (18951 hom.)
• Consequence: SERPINB3 NM_006919.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.54

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049354434).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB3	NM_006919.3	c.1052G>C	p.Gly351Ala	missense_variant	8/8	ENST00000283752.10	NP_008850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB3	ENST00000283752.10	c.1052G>C	p.Gly351Ala	missense_variant	8/8	1	NM_006919.3	ENSP00000283752.5
SERPINB3	ENST00000332821.8	c.896G>C	p.Gly299Ala	missense_variant	7/7	1		ENSP00000329498.8
SERPINB11	ENST00000489748	c.-214C>G		5_prime_UTR_premature_start_codon_gain_variant	2/7	2		ENSP00000480275.1
SERPINB11	ENST00000489748	c.-214C>G		5_prime_UTR_variant	2/7	2		ENSP00000480275.1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 20768 AN: 139370 Hom.: 1616 Cov.: 31

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.166 AC: 41100 AN: 247536 Hom.: 3762 AF XY: 0.166 AC XY: 22350 AN XY: 134236

Gnomad AFR exome AF: 0.0809

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.158 AC: 230485 AN: 1461686 Hom.: 18951 Cov.: 33 AF XY: 0.159 AC XY: 115896 AN XY: 727138

Gnomad4 AFR exome AF: 0.0607

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.149 AC: 20776 AN: 139446 Hom.: 1619 Cov.: 31 AF XY: 0.149 AC XY: 10204 AN XY: 68356

Gnomad4 AFR AF: 0.0896

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.169

Alfa AF: 0.155 Hom.: 1535

Bravo AF: 0.140

TwinsUK AF: 0.149 AC: 551

ALSPAC AF: 0.146 AC: 564

ESP6500AA AF: 0.0803 AC: 354

ESP6500EA AF: 0.164 AC: 1407

ExAC AF: 0.159 AC: 19241

Asia WGS AF: 0.120 AC: 409 AN: 3432

EpiCase AF: 0.177

EpiControl AF: 0.170

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0020
DANN	Benign	0.45
DEOGEN2	Benign	0.069	T;.
Eigen	Benign	-2.7
Eigen_PC	Benign	-2.8
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.19	T;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.63	N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.32	N;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;T
Sift4G	Benign	0.83	T;T
Polyphen		0.0	B;B
Vest4		0.038
MPC		0.025
ClinPred		0.00023	T
GERP RS		-6.0
Varity_R		0.12
gMVP		0.25

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: rs3180227; hg19: chr18-61323012; COSMIC: COSV52190544;