18-63658581-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006919.3(SERPINB3):c.401T>C(p.Val134Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0116 in 1,592,104 control chromosomes in the GnomAD database, including 297 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V134I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (17 hom., cov: 31)
  • Exomes 𝑓: 0.012 (280 hom.)
• Consequence: SERPINB3 NM_006919.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.68

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013031602).
• BP6: Variant 18-63658581-A-G is Benign according to our data. Variant chr18-63658581-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2648793.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00983 (1488/151344) while in subpopulation NFE AF= 0.016 (1078/67322). AF 95% confidence interval is 0.0152. There are 17 homozygotes in gnomad4. There are 673 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB3	NM_006919.3	c.401T>C	p.Val134Ala	missense_variant	5/8	ENST00000283752.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB3	ENST00000283752.10	c.401T>C	p.Val134Ala	missense_variant	5/8	1	NM_006919.3	P1
SERPINB3	ENST00000332821.8	c.401T>C	p.Val134Ala	missense_variant	5/7	1
SERPINB11	ENST00000489748.5	c.-16+2605A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1488 AN: 151226 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.0310

Gnomad AMR AF: 0.00856

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00880

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.00725

GnomAD3 exomes AF: 0.00177 AC: 442 AN: 250354 Hom.: 2 AF XY: 0.00184 AC XY: 249 AN XY: 135354

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.0118 AC: 16939 AN: 1440760 Hom.: 280 Cov.: 30 AF XY: 0.0115 AC XY: 8225 AN XY: 717146

Gnomad4 AFR exome AF: 0.00225

Gnomad4 AMR exome AF: 0.00582

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00384

Gnomad4 FIN exome AF: 0.00820

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00983 AC: 1488 AN: 151344 Hom.: 17 Cov.: 31 AF XY: 0.00910 AC XY: 673 AN XY: 73992

Gnomad4 AFR AF: 0.00263

Gnomad4 AMR AF: 0.00848

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00880

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.00717

Alfa AF: 0.00821 Hom.: 3

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

SERPINB3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	16
Dann	Benign	0.84
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.28
Sift	Benign	0.20	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0020	B;B
Vest4		0.14
MVP		0.74
MPC		0.030
ClinPred		0.020	T
GERP RS		0.71
Varity_R		0.32
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148254791; hg19: chr18-61325815;