NM_015065.3:c.5494C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015065.3(EXPH5):c.5494C>G(p.Arg1832Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,552 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 11 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 23 hom. )

Consequence

EXPH5
NM_015065.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.107

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025263429).

BP6

Variant 11-108510013-G-C is Benign according to our data. Variant chr11-108510013-G-C is described in ClinVar as [Benign]. Clinvar id is 777652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00853 (1299/152268) while in subpopulation AFR AF= 0.03 (1244/41534). AF 95% confidence interval is 0.0286. There are 11 homozygotes in gnomad4. There are 612 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXPH5	NM_015065.3 link	c.5494C>G	p.Arg1832Gly	missense_variant	Exon 6 of 6	ENST00000265843.9	NP_055880.2	Q8NEV8-1Q149M6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EXPH5	ENST00000265843.9 link	c.5494C>G	p.Arg1832Gly	missense_variant	Exon 6 of 6	1	NM_015065.3	ENSP00000265843.4	Q8NEV8-1
EXPH5	ENST00000525344.5 link	c.5473C>G	p.Arg1825Gly	missense_variant	Exon 7 of 7	1		ENSP00000432546.1	Q8NEV8-2
EXPH5	ENST00000526312.5 link	c.*66C>G		downstream_gene_variant		1		ENSP00000432683.1	E9PPH6

Frequencies

GnomAD3 genomes

AF:

0.00852

AC:

1296

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0300

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

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:

0.000103

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00199

AC:

498

AN:

250760

Hom.:

AF XY:

0.00137

AC XY:

186

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.000668

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000851

AC:

1244

AN:

1461284

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

498

AN XY:

726930

show subpopulations

Gnomad4 AFR exome

AF:

0.0324

Gnomad4 AMR exome

AF:

0.000986

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.00853

AC:

1299

AN:

152268

Hom.:

Cov.:

AF XY:

0.00822

AC XY:

612

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0300

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.00962

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0304

AC:

134

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00256

AC:

311

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EXPH5-related disorder

Benign:1

Mar 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

0.97

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.10

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.94

PrimateAI

Benign

0.17

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.075

Sift

Benign

0.083

T;T

Sift4G

Benign

0.22

T;T

Vest4

0.070

MVP

0.14

MPC

0.045

ClinPred

0.0037

GERP RS

0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.16

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