18-63979835-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002640.4(SERPINB8):c.203G>A(p.Arg68Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 1,613,444 control chromosomes in the GnomAD database, including 73,670 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.36 (11361 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62309 hom.)
• Consequence: SERPINB8 NM_002640.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.36

Genes affected

SERPINB8 (HGNC:8952): (serpin family B member 8) The protein encoded by this gene is a member of the ov-serpin family of serine protease inhibitors. The encoded protein is produced by platelets and can bind to and inhibit the function of furin, a serine protease involved in platelet functions. In addition, this protein has been found to enhance the mechanical stability of cell-cell adhesion in the skin, and defects in this gene have been associated with an autosomal-recessive form of exfoliative ichthyosis. [provided by RefSeq, Jan 2017]

HMSD (HGNC:23037): (histocompatibility minor serpin domain containing) This gene encodes a serpin-domain containing protein that may function as a serine protease inhibitor. This gene is primarily expressed in cells of myeloid lineage. A polymorphism in this gene may result in the expression a splice variant that encodes a minor histocompatibility antigen. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.19396855E-5).
• BP6: Variant 18-63979835-G-A is Benign according to our data. Variant chr18-63979835-G-A is described in ClinVar as [Benign]. Clinvar id is 1262057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB8	NM_002640.4	c.203G>A	p.Arg68Gln	missense_variant	3/7	ENST00000397985.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB8	ENST00000397985.7	c.203G>A	p.Arg68Gln	missense_variant	3/7	1	NM_002640.4	P1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54692 AN: 151890 Hom.: 11335 Cov.: 32

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.299

GnomAD3 exomes AF: 0.291 AC: 73105 AN: 251286 Hom.: 11735 AF XY: 0.283 AC XY: 38420 AN XY: 135816

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.183

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.344

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.286 AC: 417264 AN: 1461436 Hom.: 62309 Cov.: 34 AF XY: 0.282 AC XY: 204717 AN XY: 727066

Gnomad4 AFR exome AF: 0.586

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.214

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.283

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.360 AC: 54766 AN: 152008 Hom.: 11361 Cov.: 32 AF XY: 0.355 AC XY: 26361 AN XY: 74306

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.189

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.302

Alfa AF: 0.321 Hom.: 6994

Bravo AF: 0.367

TwinsUK AF: 0.280 AC: 1040

ALSPAC AF: 0.283 AC: 1089

ESP6500AA AF: 0.573 AC: 2526

ESP6500EA AF: 0.280 AC: 2409

ExAC AF: 0.301 AC: 36517

Asia WGS AF: 0.232 AC: 811 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Peeling skin syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	4.3
Dann	Benign	0.79
DEOGEN2	Benign	0.082	T;T;.;.;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.041	N
MetaRNN	Benign	0.000012	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.98	N;N;.;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	2.2	N;N;.;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T;.;T;T;T
Sift4G	Benign	0.91	T;T;.;T;T;T
Polyphen		0.0	B;B;.;.;.;.
Vest4		0.013
MPC		0.015
ClinPred		0.00088	T
GERP RS		-5.6
Varity_R		0.030
gMVP		0.059

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: rs1944270; hg19: chr18-61647069; COSMIC: COSV54639058;