18-63655778-C-G

Variant names:

• chr18-63655778-C-G
• rs3180227
• NM_006919.3:c.1052G>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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: 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
• Publications: 29 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006919.3. 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>C	p.Gly351Ala	missense	Exon 8 of 8	NP_008850.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB3	ENST00000283752.10	TSL:1 MANE Select	c.1052G>C	p.Gly351Ala	missense	Exon 8 of 8	ENSP00000283752.5
	SERPINB3	ENST00000332821.8	TSL:1	c.896G>C	p.Gly299Ala	missense	Exon 7 of 7	ENSP00000329498.8
	SERPINB11	ENST00000489748.5	TSL:2	c.-214C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	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

GnomAD2 exomes AF: 0.166 AC: 41100 AN: 247536 AF XY: 0.166

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 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

African (AFR) AF: 0.0607 AC: 2031 AN: 33470

American (AMR) AF: 0.216 AC: 9657 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6846 AN: 26120

East Asian (EAS) AF: 0.107 AC: 4232 AN: 39692

South Asian (SAS) AF: 0.179 AC: 15463 AN: 86250

European-Finnish (FIN) AF: 0.142 AC: 7566 AN: 53416

Middle Eastern (MID) AF: 0.214 AC: 1232 AN: 5764

European-Non Finnish (NFE) AF: 0.156 AC: 173736 AN: 1111898

Other (OTH) AF: 0.161 AC: 9722 AN: 60382

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

African (AFR) AF: 0.0896 AC: 2663 AN: 29710

American (AMR) AF: 0.195 AC: 2905 AN: 14930

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 947 AN: 3410

East Asian (EAS) AF: 0.101 AC: 522 AN: 5176

South Asian (SAS) AF: 0.169 AC: 811 AN: 4804

European-Finnish (FIN) AF: 0.143 AC: 1505 AN: 10490

Middle Eastern (MID) AF: 0.198 AC: 57 AN: 288

European-Non Finnish (NFE) AF: 0.159 AC: 10767 AN: 67746

Other (OTH) AF: 0.169 AC: 336 AN: 1986

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 v4.9

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
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.63	N
PhyloP100		-2.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.025
ClinPred		0.00023	T
GERP RS		-6.0
Varity_R		0.12
gMVP		0.25
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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