chr18-63639663-T-G

Variant names:

• chr18-63639663-T-G
• NM_002974.4:c.583A>C

Variant summary

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

The NM_002974.4(SERPINB4):​c.583A>C​(p.Thr195Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,324 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SERPINB4 NM_002974.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89

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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB4	NM_002974.4	c.583A>C	p.Thr195Pro	missense_variant	Exon 6 of 8	ENST00000341074.10	NP_002965.1
SERPINB4	NM_175041.2	c.583A>C	p.Thr195Pro	missense_variant	Exon 6 of 8		NP_778206.1
SERPINB4	XM_011526138.2	c.583A>C	p.Thr195Pro	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.583A>C	p.Thr195Pro	missense_variant	Exon 6 of 8	1	NM_002974.4	ENSP00000343445.5
SERPINB4	ENST00000413673.5	c.586A>C	p.Thr196Pro	missense_variant	Exon 5 of 7	1		ENSP00000398645.1
SERPINB4	ENST00000436264.1	c.454A>C	p.Thr152Pro	missense_variant	Exon 5 of 6	5		ENSP00000399796.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457324 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725206

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	4.2	H;.
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.63
MutPred		0.85		Gain of glycosylation at T195 (P = 0.0154);.;
MVP		0.63
MPC		0.061
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.73
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-61306897;