18-63657314-A-G

Position:

• chr18-63657314-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006919.3(SERPINB3):​c.568T>C​(p.Phe190Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINB3 NM_006919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB3	NM_006919.3	c.568T>C	p.Phe190Leu	missense_variant	6/8	ENST00000283752.10	NP_008850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB3	ENST00000283752.10	c.568T>C	p.Phe190Leu	missense_variant	6/8	1	NM_006919.3	ENSP00000283752	P1
SERPINB3	ENST00000332821.8	c.568T>C	p.Phe190Leu	missense_variant	6/7	1		ENSP00000329498
SERPINB11	ENST00000489748.5	c.-16+1338A>G		intron_variant		2		ENSP00000480275

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.568T>C (p.F190L) alteration is located in exon 6 (coding exon 5) of the SERPINB3 gene. This alteration results from a T to C substitution at nucleotide position 568, causing the phenylalanine (F) at amino acid position 190 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Uncertain	0.47
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.96		Loss of methylation at K192 (P = 0.0947);Loss of methylation at K192 (P = 0.0947);
MVP		0.91
MPC		0.16
ClinPred		0.97	D
GERP RS		2.7
Varity_R		0.89
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-61324548;