18-63657278-G-A

Variant names:

• chr18-63657278-G-A
• rs145445388
• NM_006919.3:c.604C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006919.3(SERPINB3):​c.604C>T​(p.Pro202Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,562,818 control chromosomes in the GnomAD database, including 5 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: SERPINB3 NM_006919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.363

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062802196).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB3	NM_006919.3	c.604C>T	p.Pro202Ser	missense_variant	Exon 6 of 8	ENST00000283752.10	NP_008850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB3	ENST00000283752.10	c.604C>T	p.Pro202Ser	missense_variant	Exon 6 of 8	1	NM_006919.3	ENSP00000283752.5
SERPINB3	ENST00000332821.8	c.604C>T	p.Pro202Ser	missense_variant	Exon 6 of 7	1		ENSP00000329498.8
SERPINB11	ENST00000489748.5	c.-16+1302G>A		intron_variant	Intron 2 of 6	2		ENSP00000480275.1

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 151936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000422 AC: 102 AN: 241506 Hom.: 0 AF XY: 0.000413 AC XY: 54 AN XY: 130610

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000247

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000785

Gnomad OTH exome AF: 0.000518

GnomAD4 exome AF: 0.00114 AC: 1605 AN: 1410882 Hom.: 5 Cov.: 27 AF XY: 0.00107 AC XY: 752 AN XY: 702546

Gnomad4 AFR exome AF: 0.000187

Gnomad4 AMR exome AF: 0.000331

Gnomad4 ASJ exome AF: 0.0000395

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.000612 AC: 93 AN: 151936 Hom.: 0 Cov.: 32 AF XY: 0.000607 AC XY: 45 AN XY: 74182

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000919

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.000631

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000321 AC: 39

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604C>T (p.P202S) alteration is located in exon 6 (coding exon 5) of the SERPINB3 gene. This alteration results from a C to T substitution at nucleotide position 604, causing the proline (P) at amino acid position 202 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.065	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.18	T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.12	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.23	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.013	D;T
Sift4G	Uncertain	0.0040	D;T
Polyphen		0.54	P;P
Vest4		0.13
MVP		0.78
MPC		0.024
ClinPred		0.019	T
GERP RS		1.8
Varity_R		0.19
gMVP		0.69

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: rs145445388; hg19: chr18-61324512;