chr18-63639643-C-A

Variant names:

• chr18-63639643-C-A
• rs140456610
• NM_002974.4:c.603G>T

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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SERPINB4 NM_002974.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.902

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]

ACMG classification

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	c.603G>T	p.Trp201Cys	missense_variant	Exon 6 of 8	ENST00000341074.10	NP_002965.1
SERPINB4	NM_175041.2	c.603G>T	p.Trp201Cys	missense_variant	Exon 6 of 8		NP_778206.1
SERPINB4	XM_011526138.2	c.603G>T	p.Trp201Cys	missense_variant	Exon 6 of 8		XP_011524440.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248786 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134838

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: 2 AN: 1448320 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 721366

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.: 32

ExAC AF: 0.00000824 AC: 1

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	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	-0.086	T
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	D
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

Other links and lift over

dbSNP: rs140456610; hg19: chr18-61306877;