rs193921093

Positions:

• chr18-63639770-A-T

Variant summary

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

The NM_002974.4(SERPINB4):​c.476T>A​(p.Ile159Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SERPINB4 NM_002974.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.09

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 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, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB4	NM_002974.4	c.476T>A	p.Ile159Asn	missense_variant	6/8	ENST00000341074.10	NP_002965.1
SERPINB4	NM_175041.2	c.476T>A	p.Ile159Asn	missense_variant	6/8		NP_778206.1
SERPINB4	XM_011526138.2	c.476T>A	p.Ile159Asn	missense_variant	6/8		XP_011524440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB4	ENST00000341074.10	c.476T>A	p.Ile159Asn	missense_variant	6/8	1	NM_002974.4	ENSP00000343445	P1
SERPINB4	ENST00000413673.5	c.482T>A	p.Ile161Asn	missense_variant	5/7	1		ENSP00000398645
SERPINB4	ENST00000436264.1	c.347T>A	p.Ile116Asn	missense_variant	5/6	5		ENSP00000399796

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455906 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724214

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.9	H;.
MutationTaster	Benign	1.0	D;D
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.85		Gain of disorder (P = 0.0157);.;
MVP		0.58
MPC		0.059
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.84
gMVP		0.70

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: rs193921093; hg19: chr18-61307004; COSMIC: COSV61984229; COSMIC: COSV61984229;