18-63804288-C-T

Variant names:

• chr18-63804288-C-T
• rs142859678
• NM_003784.4:c.796C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_003784.4(SERPINB7):​c.796C>T​(p.Arg266*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,605,018 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: SERPINB7 NM_003784.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 0.447
• Publications: 34 publications found

Genes affected

SERPINB7 (HGNC:13902): (serpin family B member 7) This gene encodes a member of a family of proteins which function as protease inhibitors. Expression of this gene is upregulated in IgA nephropathy and mutations have been found to cause palmoplantar keratoderma, Nagashima type. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

SERPINB7 Gene-Disease associations (from GenCC):

• palmoplantar keratoderma, Nagashima type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.304 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 18-63804288-C-T is Pathogenic according to our data. Variant chr18-63804288-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 102446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003784.4. 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
	SERPINB7	NM_003784.4	MANE Select	c.796C>T	p.Arg266*	stop_gained	Exon 8 of 8	NP_003775.1
	SERPINB7	NM_001040147.3		c.796C>T	p.Arg266*	stop_gained	Exon 8 of 8	NP_001035237.1
	SERPINB7	NM_001261830.2		c.796C>T	p.Arg266*	stop_gained	Exon 8 of 8	NP_001248759.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB7	ENST00000398019.7	TSL:1 MANE Select	c.796C>T	p.Arg266*	stop_gained	Exon 8 of 8	ENSP00000381101.2
	SERPINB7	ENST00000336429.6	TSL:1	c.796C>T	p.Arg266*	stop_gained	Exon 8 of 8	ENSP00000337212.2
	SERPINB7	ENST00000546027.5	TSL:2	c.796C>T	p.Arg266*	stop_gained	Exon 8 of 8	ENSP00000444861.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00848

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000550 AC: 134 AN: 243522 AF XY: 0.000510

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00692

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000243 AC: 353 AN: 1452808 Hom.: 0 Cov.: 29 AF XY: 0.000253 AC XY: 183 AN XY: 722538

African (AFR) AF: 0.0000304 AC: 1 AN: 32900

American (AMR) AF: 0.00 AC: 0 AN: 43222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25506

East Asian (EAS) AF: 0.00764 AC: 303 AN: 39682

South Asian (SAS) AF: 0.000190 AC: 16 AN: 84314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1108482

Other (OTH) AF: 0.000200 AC: 12 AN: 60010

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74422

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00850 AC: 44 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000420 Hom.: 3

Bravo AF: 0.000434

ExAC AF: 0.000519 AC: 63

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Palmoplantar keratoderma, Nagashima type (9)
3	-	-	not provided (3)
1	-	-	Palmoplantar keratodermas (1)
1	-	-	SERPINB7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.061	N
PhyloP100		0.45
Vest4		0.69
GERP RS		4.8
Mutation Taster		=25/175	disease causing (ClinVar)

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: rs142859678; hg19: chr18-61471522; COSMIC: COSV100321096;