chr18-63637751-T-A

Variant names:

• chr18-63637751-T-A
• rs1438171301
• NM_002974.4:c.1141A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002974.4(SERPINB4):​c.1141A>T​(p.Ile381Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I381L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SERPINB4 NM_002974.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002974.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB4	NM_002974.4	MANE Select	c.1141A>T	p.Ile381Phe	missense	Exon 8 of 8	NP_002965.1	P48594
	SERPINB4	NM_175041.2		c.1078A>T	p.Ile360Phe	missense	Exon 8 of 8	NP_778206.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB4	ENST00000341074.10	TSL:1 MANE Select	c.1141A>T	p.Ile381Phe	missense	Exon 8 of 8	ENSP00000343445.5	P48594
	SERPINB4	ENST00000413673.5	TSL:1	c.1081A>T	p.Ile361Phe	missense	Exon 7 of 7	ENSP00000398645.1	H0Y5H9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460086 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726272

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 85996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111048

Other (OTH) AF: 0.00 AC: 0 AN: 60308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.095
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		0.54
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.76		Gain of catalytic residue at I381 (P = 0.0058)
MVP		0.50
MPC		0.059
ClinPred		0.90	D
GERP RS		2.0
Varity_R		0.52
gMVP		0.69
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs1438171301; hg19: chr18-61304985;