dbSNP rs140456610: SERPINB4:p.Trp201Cys (chr18-63639643-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002974.4(SERPINB4):c.603G>T(p.Trp201Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,320 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W201L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SERPINB4
NM_002974.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.902

Variant links:

Genes affected

SERPINB4 (HGNC:10570): (serpin family B member 4) The protein encoded by this gene is a member of the serpin family of serine protease inhibitors. The encoded protein is highly expressed in many tumor cells and can inactivate granzyme M, an enzyme that kills tumor cells. This protein, along with serpin B3, can be processed into smaller fragments that aggregate to form an autoantigen in psoriasis, probably by causing chronic inflammation. [provided by RefSeq, Jan 2017]

SERPINB4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB4	NM_002974.4 link	c.603G>T	p.Trp201Cys	missense_variant	Exon 6 of 8	ENST00000341074.10	NP_002965.1
SERPINB4	NM_175041.2 link	c.603G>T	p.Trp201Cys	missense_variant	Exon 6 of 8		NP_778206.1
SERPINB4	XM_011526138.2 link	c.603G>T	p.Trp201Cys	missense_variant	Exon 6 of 8		XP_011524440.1	P48594

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINB4	ENST00000341074.10 link	c.603G>T	p.Trp201Cys	missense_variant	Exon 6 of 8	1	NM_002974.4	ENSP00000343445.5	P48594
SERPINB4	ENST00000413673.5 link	c.606G>T	p.Trp202Cys	missense_variant	Exon 5 of 7	1		ENSP00000398645.1	H0Y5H9
SERPINB4	ENST00000436264.1 link	c.474G>T	p.Trp158Cys	missense_variant	Exon 5 of 6	5		ENSP00000399796.1	C9JZ65

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248786

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448320

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721366

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Uncertain

-0.086

MutationAssessor

Uncertain

2.6

M;.

PROVEAN

Pathogenic

-11

D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.18

T;.

Polyphen

1.0

D;.

Vest4

0.39

MutPred

0.61

Loss of MoRF binding (P = 0.0295);.;

MVP

0.53

MPC

0.057

ClinPred

0.96

GERP RS

4.5

Varity_R

0.29

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over