11-108510085-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_015065.3(EXPH5):c.5422C>T(p.Arg1808Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,611,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

EXPH5
NM_015065.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: -0.634

Variant links:

Genes affected

EXPH5 (HGNC:30578): (exophilin 5) The protein encoded by this gene is a member of the synaptotagmin-like protein (Slp) family lacking a C2 domain. It contains an N-terminal synaptotagmin-like homology domain (SHD), and is a ras-related protein Rab-27B effector protein. This protein is thought to be involved in exosome secretion and intracellular vesicle trafficking. Reduced expression of this gene results in keratin filament defects. Mutations in this gene have been associated with some cases of epidermolysis bullosa, an inherited skin fragility disorder. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

EXPH5 links:

LOC112267909 (HGNC:):

LOC112267909 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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 0.0918 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-108510085-G-A is Pathogenic according to our data. Variant chr11-108510085-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1805039.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr11-108510085-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXPH5	NM_015065.3 linkuse as main transcript	c.5422C>T	p.Arg1808Ter	stop_gained	6/6	ENST00000265843.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXPH5	ENST00000265843.9 linkuse as main transcript	c.5422C>T	p.Arg1808Ter	stop_gained	6/6	1	NM_015065.3	P4	Q8NEV8-1
EXPH5	ENST00000525344.5 linkuse as main transcript	c.5401C>T	p.Arg1801Ter	stop_gained	7/7	1		A2	Q8NEV8-2
EXPH5	ENST00000526312.5 linkuse as main transcript	c.5194C>T	p.Arg1732Ter	stop_gained	6/6	1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000562

AC:

AN:

249014

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134594

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.0000666

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000678

AC:

AN:

1459602

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

726076

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000583

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000738

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000552

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a reported mechanism of disease in this gene and is associated with autosomal recessive nonspecific epidermolysis bullosa (MIM#615028; PMID: 27730671). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 14 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other variants predicted to result in a truncated protein comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two truncations downstream have been reported. p.(Pro1929Leufs*8) has been found in two families with recessive epidermolysis bullosa (PMIDs: 23176819, 32176379) and is also reported pathogenic in ClinVar, and p.(Phe1897Serfs*2) has been reported in an individual with fragile skin among other features such as intellectual disability (LOVD). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an individual. It was identified in a consanguineous family, in a homozygous individual who was also homozygous for p.(Thr68LeufsTer106) in the COL17A1 gene and presented with a complex blended phenotype (EB simplex and junctional EB) explained by both genes (PMID: 30016581). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Immunofluorescence staining showed no Exph5 protein in skin, however, the antibodies used were targeting the C-terminal, which is expected to be deleted in this truncated protein that is not predicted to result in nonsense mediated decay (PMID: 30016581). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 10, 2022

This sequence change creates a premature translational stop signal (p.Arg1808*) in the EXPH5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acid(s) of the EXPH5 protein. This variant is present in population databases (rs142805294, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of EXPH5-related conditions (PMID: 28830826). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Uncertain

0.070

Cadd

Pathogenic

Dann

Benign

0.90

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.046

MutationTaster

Benign

1.0

D;D;D;D

Vest4

0.074

GERP RS

-4.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over