18-63643180-T-C

Variant names:

• chr18-63643180-T-C
• rs759766809
• NM_002974.4:c.203A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002974.4(SERPINB4):​c.203A>G​(p.Glu68Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,040 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: SERPINB4 NM_002974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.930

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06957042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB4	NM_002974.4	c.203A>G	p.Glu68Gly	missense_variant	Exon 3 of 8	ENST00000341074.10	NP_002965.1
SERPINB4	NM_175041.2	c.203A>G	p.Glu68Gly	missense_variant	Exon 3 of 8		NP_778206.1
SERPINB4	XM_011526138.2	c.203A>G	p.Glu68Gly	missense_variant	Exon 3 of 8		XP_011524440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB4	ENST00000341074.10	c.203A>G	p.Glu68Gly	missense_variant	Exon 3 of 8	1	NM_002974.4	ENSP00000343445.5
SERPINB4	ENST00000413673.5	c.206A>G	p.Glu69Gly	missense_variant	Exon 2 of 7	1		ENSP00000398645.1
SERPINB4	ENST00000498496.1	n.276A>G		non_coding_transcript_exon_variant	Exon 3 of 3	1
SERPINB4	ENST00000436264.1	c.203A>G	p.Glu68Gly	missense_variant	Exon 3 of 6	5		ENSP00000399796.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000140 AC: 35 AN: 250692 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135436

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1460936 Hom.: 1 Cov.: 32 AF XY: 0.000136 AC XY: 99 AN XY: 726732

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74296

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000288 AC: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.203A>G (p.E68G) alteration is located in exon 3 (coding exon 2) of the SERPINB4 gene. This alteration results from a A to G substitution at nucleotide position 203, causing the glutamic acid (E) at amino acid position 68 to be replaced by a glycine (G). 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	0.067
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.6
DANN	Benign	0.71
DEOGEN2	Benign	0.098	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.48	N;.
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.17
Sift	Benign	0.39	T;T
Sift4G	Benign	0.38	T;.
Polyphen		0.0010	B;.
Vest4		0.074
MVP		0.32
MPC		0.0096
ClinPred		0.013	T
GERP RS		-0.49
Varity_R		0.020
gMVP		0.12

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: rs759766809; hg19: chr18-61310414; COSMIC: COSV61985694; COSMIC: COSV61985694;