chr18-63637975-T-C

Variant names:

• chr18-63637975-T-C
• rs137899169
• NM_002974.4:c.917A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002974.4(SERPINB4):​c.917A>G​(p.Asn306Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000236 in 1,613,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N306D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: SERPINB4 NM_002974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08513537).

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.917A>G	p.Asn306Ser	missense	Exon 8 of 8	NP_002965.1	P48594
	SERPINB4	NM_175041.2		c.854A>G	p.Asn285Ser	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.917A>G	p.Asn306Ser	missense	Exon 8 of 8	ENSP00000343445.5	P48594
	SERPINB4	ENST00000413673.5	TSL:1	c.857A>G	p.Asn286Ser	missense	Exon 7 of 7	ENSP00000398645.1	H0Y5H9

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000179 AC: 45 AN: 251094 AF XY: 0.000177

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000240 AC: 351 AN: 1461486 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 176 AN XY: 727054

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.0000448 AC: 2 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.000300 AC: 334 AN: 1111796

Other (OTH) AF: 0.000166 AC: 10 AN: 60376

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152208 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8 AN XY: 74420

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67986

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000222 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.6
DANN	Benign	0.91
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.57	N
PhyloP100		4.0
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.049	D
Sift4G	Benign	0.082	T
Polyphen		0.030	B
Vest4		0.021
MVP		0.36
MPC		0.010
ClinPred		0.026	T
GERP RS		3.3
Varity_R		0.039
gMVP		0.14
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs137899169; hg19: chr18-61305209;