chr18-63655764-G-A

Variant names:

• chr18-63655764-G-A
• rs73962331
• NM_006919.3:c.1066C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 2 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 -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB3	NM_006919.3	MANE Select	c.1066C>T	p.Pro356Ser	missense	Exon 8 of 8	NP_008850.1	P29508-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB3	ENST00000283752.10	TSL:1 MANE Select	c.1066C>T	p.Pro356Ser	missense	Exon 8 of 8	ENSP00000283752.5	P29508-1
	SERPINB3	ENST00000332821.8	TSL:1	c.910C>T	p.Pro304Ser	missense	Exon 7 of 7	ENSP00000329498.8	P29508-2
	SERPINB11	ENST00000489748.5	TSL:2	c.-228G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000480275.1	A0A087WWJ8

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

GnomAD2 exomes AF: 0.00576 AC: 1434 AN: 249090 AF XY: 0.00411

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 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

African (AFR) AF: 0.171 AC: 5718 AN: 33434

American (AMR) AF: 0.00996 AC: 445 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00812 AC: 212 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00232 AC: 200 AN: 86250

European-Finnish (FIN) AF: 0.00515 AC: 275 AN: 53410

Middle Eastern (MID) AF: 0.0262 AC: 151 AN: 5764

European-Non Finnish (NFE) AF: 0.00130 AC: 1451 AN: 1111922

Other (OTH) AF: 0.0131 AC: 792 AN: 60380

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

African (AFR) AF: 0.166 AC: 6895 AN: 41498

American (AMR) AF: 0.0146 AC: 223 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.00621 AC: 66 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 68010

Other (OTH) AF: 0.0346 AC: 73 AN: 2112

Alfa AF: 0.0220 Hom.: 174

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.51	N
PhyloP100		-0.16
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.024
ClinPred		0.00030	T
GERP RS		0.50
Varity_R		0.064
gMVP		0.17
Mutation Taster		=100/0	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: rs73962331; hg19: chr18-61322998;