11-108509712-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015065.3(EXPH5):c.5795C>T(p.Pro1932Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

EXPH5
NM_015065.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.834

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, Genomics England PanelApp

EXPH5 links:

ENSG00000296559 (HGNC:):

ENSG00000296559 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054133147).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015065.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXPH5	NM_015065.3	MANE Select	c.5795C>T	p.Pro1932Leu	missense	Exon 6 of 6	NP_055880.2	Q8NEV8-1
EXPH5	NM_001441059.1		c.5792C>T	p.Pro1931Leu	missense	Exon 6 of 6	NP_001427988.1
EXPH5	NM_001308019.2		c.5774C>T	p.Pro1925Leu	missense	Exon 7 of 7	NP_001294948.1	Q8NEV8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXPH5	ENST00000265843.9	TSL:1 MANE Select	c.5795C>T	p.Pro1932Leu	missense	Exon 6 of 6	ENSP00000265843.4	Q8NEV8-1
EXPH5	ENST00000525344.5	TSL:1	c.5774C>T	p.Pro1925Leu	missense	Exon 7 of 7	ENSP00000432546.1	Q8NEV8-2
ENSG00000296559	ENST00000740313.1		n.325-5599G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000244

AC:

AN:

246284

AF XY:

0.0000375

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1457042

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724778

show subpopulations

African (AFR)

AF:

0.000181

AC:

AN:

33118

American (AMR)

AF:

0.00

AC:

AN:

43482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25828

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

85132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110648

Other (OTH)

AF:

0.0000166

AC:

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.9

(source)

DANN

Benign

0.54

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.074

M_CAP

Benign

0.018

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

PhyloP100

0.83

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.059

Sift

Benign

0.23

Sift4G

Benign

0.20

Vest4

0.026

MVP

0.39

MPC

0.21

ClinPred

0.038

GERP RS

2.8

gMVP

0.12

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over