chr11-108509554-T-C

Position:

chr11-108509554-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_015065.3(EXPH5):c.5953A>G(p.Lys1985Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00509 in 1,556,862 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 35 hom. )

Consequence

EXPH5
NM_015065.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.83

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 -9 ACMG points.

BP6

Variant 11-108509554-T-C is Benign according to our data. Variant chr11-108509554-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 719499.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr11-108509554-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00286 (435/152342) while in subpopulation NFE AF= 0.00506 (344/68022). AF 95% confidence interval is 0.00462. There are 1 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXPH5	NM_015065.3 linkuse as main transcript	c.5953A>G	p.Lys1985Glu	missense_variant	6/6	ENST00000265843.9	NP_055880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXPH5	ENST00000265843.9 linkuse as main transcript	c.5953A>G	p.Lys1985Glu	missense_variant	6/6	1	NM_015065.3	ENSP00000265843	P4	Q8NEV8-1
EXPH5	ENST00000525344.5 linkuse as main transcript	c.5932A>G	p.Lys1978Glu	missense_variant	7/7	1		ENSP00000432546	A2	Q8NEV8-2

Frequencies

GnomAD3 genomes

AF:

0.00286

AC:

435

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00506

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00270

AC:

538

AN:

199500

Hom.:

AF XY:

0.00259

AC XY:

277

AN XY:

106908

show subpopulations

Gnomad AFR exome

AF:

0.00109

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00198

Gnomad NFE exome

AF:

0.00481

Gnomad OTH exome

AF:

0.00172

GnomAD4 exome

AF:

0.00533

AC:

7482

AN:

1404520

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

3587

AN XY:

695222

show subpopulations

Gnomad4 AFR exome

AF:

0.000743

Gnomad4 AMR exome

AF:

0.000315

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00156

Gnomad4 NFE exome

AF:

0.00664

Gnomad4 OTH exome

AF:

0.00226

GnomAD4 genome

AF:

0.00286

AC:

435

AN:

152342

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

199

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00506

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00414

Hom.:

Bravo

AF:

0.00289

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00246

AC:

298

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.037

MetaRNN

Benign

0.0088

T;T

MetaSVM

Uncertain

-0.11

MutationTaster

Benign

0.83

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0090

D;D

Vest4

0.33

MVP

0.66

MPC

0.27

ClinPred

0.029

GERP RS

5.8

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: -13

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