chr11-108509797-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015065.3(EXPH5):ā€‹c.5710T>Cā€‹(p.Ser1904Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

EXPH5
NM_015065.3 missense

Scores

3
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.91
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EXPH5NM_015065.3 linkuse as main transcriptc.5710T>C p.Ser1904Pro missense_variant 6/6 ENST00000265843.9 NP_055880.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EXPH5ENST00000265843.9 linkuse as main transcriptc.5710T>C p.Ser1904Pro missense_variant 6/61 NM_015065.3 ENSP00000265843 P4Q8NEV8-1
EXPH5ENST00000525344.5 linkuse as main transcriptc.5689T>C p.Ser1897Pro missense_variant 7/71 ENSP00000432546 A2Q8NEV8-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
249932
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135102
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460402
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726494
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2021The c.5710T>C (p.S1904P) alteration is located in exon 6 (coding exon 6) of the EXPH5 gene. This alteration results from a T to C substitution at nucleotide position 5710, causing the serine (S) at amino acid position 1904 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Benign
0.032
D
MetaRNN
Uncertain
0.66
D;D
MetaSVM
Benign
-0.44
T
MutationTaster
Benign
0.92
D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Benign
0.23
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0080
D;D
Vest4
0.76
MutPred
0.41
Gain of loop (P = 0.0013);.;
MVP
0.56
MPC
0.30
ClinPred
0.96
D
GERP RS
6.2
gMVP
0.65

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.

Other links and lift over

dbSNP: rs1459391622; hg19: chr11-108380524; API