chr18-63792442-AG-TAAACTTTACCT

Variant names:

• chr18-63792442-AG-TAAACTTTACCT
• rs797044479
• ENST00000398019.7:c.205_206delAGinsTAAACTTTACCT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000398019.7(SERPINB7):​c.205_206delAGinsTAAACTTTACCT​(p.Ser69LeufsTer17) variant causes a frameshift, stop gained, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S69P) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINB7 ENST00000398019.7 frameshift, stop_gained, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.37
• Publications: 2 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: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-63792442-AG-TAAACTTTACCT is Pathogenic according to our data. Variant chr18-63792442-AG-TAAACTTTACCT is described in ClinVar as Pathogenic. ClinVar VariationId is 102447.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398019.7. 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.218_219delAGinsTAAACTTTACCT	p.Gln73delinsLeuAsnPheThr???	missense splice_region	N/A	NP_003775.1	O75635-1
	SERPINB7	NM_001040147.3		c.218_219delAGinsTAAACTTTACCT	p.Gln73delinsLeuAsnPheThr???	missense splice_region	N/A	NP_001035237.1	O75635-1
	SERPINB7	NM_001261830.2		c.218_219delAGinsTAAACTTTACCT	p.Gln73delinsLeuAsnPheThr???	missense splice_region	N/A	NP_001248759.1	O75635-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB7	ENST00000398019.7	TSL:1 MANE Select	c.205_206delAGinsTAAACTTTACCT	p.Ser69LeufsTer17	frameshift stop_gained missense	Exon 3 of 8	ENSP00000381101.2	O75635-1
	SERPINB7	ENST00000336429.6	TSL:1	c.205_206delAGinsTAAACTTTACCT	p.Ser69LeufsTer17	frameshift stop_gained missense	Exon 3 of 8	ENSP00000337212.2	O75635-1
	SERPINB7	ENST00000546027.5	TSL:2	c.205_206delAGinsTAAACTTTACCT	p.Ser69LeufsTer17	frameshift stop_gained missense	Exon 3 of 8	ENSP00000444861.1	O75635-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Palmoplantar keratoderma, Nagashima type (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=10/190	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797044479; hg19: chr18-61459676;