18-63978389-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_002640.4(SERPINB8):c.81C>T(p.Asn27=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,614,156 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (165 hom.)
• Consequence: SERPINB8 NM_002640.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.13

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 18-63978389-C-T is Benign according to our data. Variant chr18-63978389-C-T is described in ClinVar as [Benign]. Clinvar id is 778775.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00749 (1140/152284) while in subpopulation SAS AF= 0.0431 (208/4824). AF 95% confidence interval is 0.0383. There are 9 homozygotes in gnomad4. There are 611 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB8	NM_002640.4	c.81C>T	p.Asn27=	synonymous_variant	2/7	ENST00000397985.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB8	ENST00000397985.7	c.81C>T	p.Asn27=	synonymous_variant	2/7	1	NM_002640.4	P1

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1138 AN: 152166 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00832 AC: 2092 AN: 251448 Hom.: 49 AF XY: 0.0100 AC XY: 1360 AN XY: 135900

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0475

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000879

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00429 AC: 6278 AN: 1461872 Hom.: 165 Cov.: 31 AF XY: 0.00553 AC XY: 4024 AN XY: 727244

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0473

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000501

Gnomad4 OTH exome AF: 0.00682

GnomAD4 genome AF: 0.00749 AC: 1140 AN: 152284 Hom.: 9 Cov.: 32 AF XY: 0.00821 AC XY: 611 AN XY: 74460

Gnomad4 AFR AF: 0.0187

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0431

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00461 Hom.: 3

Bravo AF: 0.00761

Asia WGS AF: 0.0240 AC: 84 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.16
Dann	Benign	0.48

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: rs61735438; hg19: chr18-61645623; COSMIC: COSV54640705; COSMIC: COSV54640705;