18-63655764-G-A

Position:

• chr18-63655764-G-A

Variant summary

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

The NM_006919.3(SERPINB3):​c.1066C>T​(p.Pro356Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,613,868 control chromosomes in the GnomAD database, including 1,142 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (605 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (537 hom.)
• Consequence: SERPINB3 NM_006919.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.157

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063301325).
• BP6: Variant 18-63655764-G-A is Benign according to our data. Variant chr18-63655764-G-A is described in ClinVar as [Benign]. Clinvar id is 768937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB3	NM_006919.3	c.1066C>T	p.Pro356Ser	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.1066C>T	p.Pro356Ser	missense_variant	8/8	1	NM_006919.3	ENSP00000283752.5
SERPINB3	ENST00000332821.8	c.910C>T	p.Pro304Ser	missense_variant	7/7	1		ENSP00000329498.8
SERPINB11	ENST00000489748	c.-228G>A		5_prime_UTR_premature_start_codon_gain_variant	2/7	2		ENSP00000480275.1
SERPINB11	ENST00000489748	c.-228G>A		5_prime_UTR_variant	2/7	2		ENSP00000480275.1

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7443 AN: 152080 Hom.: 604 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00621

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.00576 AC: 1434 AN: 249090 Hom.: 124 AF XY: 0.00411 AC XY: 554 AN XY: 134822

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.000759

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00632 AC: 9245 AN: 1461670 Hom.: 537 Cov.: 32 AF XY: 0.00571 AC XY: 4153 AN XY: 727138

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.00996

Gnomad4 ASJ exome AF: 0.00812

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00232

Gnomad4 FIN exome AF: 0.00515

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0490 AC: 7464 AN: 152198 Hom.: 605 Cov.: 32 AF XY: 0.0474 AC XY: 3525 AN XY: 74416

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00621

Gnomad4 NFE AF: 0.00221

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0214 Hom.: 130

Bravo AF: 0.0559

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.153 AC: 674

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.0164 AC: 1989

Asia WGS AF: 0.0120 AC: 41 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.00131

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.016
DANN	Benign	0.59
DEOGEN2	Benign	0.061	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.51	N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.52	N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0	B;B
Vest4		0.023
MPC		0.024
ClinPred		0.00030	T
GERP RS		0.50
Varity_R		0.064
gMVP		0.17

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: rs73962331; hg19: chr18-61322998;