NM_015065.3:c.5614A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_015065.3(EXPH5):c.5614A>G(p.Thr1872Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,607,842 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0046 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 53 hom. )

Consequence

EXPH5
NM_015065.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.668

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021021366).

BP6

Variant 11-108509893-T-C is Benign according to our data. Variant chr11-108509893-T-C is described in ClinVar as [Benign]. Clinvar id is 714777.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00457 (696/152274) while in subpopulation NFE AF= 0.00345 (235/68030). AF 95% confidence interval is 0.00309. There are 5 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXPH5	NM_015065.3 link	c.5614A>G	p.Thr1872Ala	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.5614A>G	p.Thr1872Ala	missense_variant	Exon 6 of 6	1	NM_015065.3	ENSP00000265843.4	Q8NEV8-1
EXPH5	ENST00000525344.5 link	c.5593A>G	p.Thr1865Ala	missense_variant	Exon 7 of 7	1		ENSP00000432546.1	Q8NEV8-2
EXPH5	ENST00000526312.5 link	c.*186A>G		downstream_gene_variant		1		ENSP00000432683.1	E9PPH6

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

696

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0411

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00345

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00567

AC:

1388

AN:

244800

Hom.:

AF XY:

0.00580

AC XY:

767

AN XY:

132326

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.000815

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000311

Gnomad FIN exome

AF:

0.0364

Gnomad NFE exome

AF:

0.00479

Gnomad OTH exome

AF:

0.00593

GnomAD4 exome

AF:

0.00384

AC:

5588

AN:

1455568

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

2766

AN XY:

723860

show subpopulations

Gnomad4 AFR exome

AF:

0.000423

Gnomad4 AMR exome

AF:

0.000715

Gnomad4 ASJ exome

AF:

0.0000777

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000683

Gnomad4 FIN exome

AF:

0.0351

Gnomad4 NFE exome

AF:

0.00309

Gnomad4 OTH exome

AF:

0.00296

GnomAD4 genome

AF:

0.00457

AC:

696

AN:

152274

Hom.:

Cov.:

AF XY:

0.00600

AC XY:

447

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0411

Gnomad4 NFE

AF:

0.00345

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00279

Hom.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00557

AC:

676

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

EXPH5-related disorder

Benign:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.37

DANN

Benign

0.23

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.041

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.90

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.012

Sift

Benign

0.37

T;T

Sift4G

Benign

0.79

T;T

Vest4

0.023

MVP

0.030

MPC

0.037

ClinPred

0.0061

GERP RS

-5.2

gMVP

0.11

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