chr11-108510028-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015065.3(EXPH5):​c.5479G>T​(p.Asp1827Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

EXPH5
NM_015065.3 missense

Scores

6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25711602).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EXPH5NM_015065.3 linkuse as main transcriptc.5479G>T p.Asp1827Tyr 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.5479G>T p.Asp1827Tyr missense_variant 6/61 NM_015065.3 ENSP00000265843 P4Q8NEV8-1
EXPH5ENST00000525344.5 linkuse as main transcriptc.5458G>T p.Asp1820Tyr missense_variant 7/71 ENSP00000432546 A2Q8NEV8-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
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 GeneticsOct 25, 2023The c.5479G>T (p.D1827Y) alteration is located in exon 6 (coding exon 6) of the EXPH5 gene. This alteration results from a G to T substitution at nucleotide position 5479, causing the aspartic acid (D) at amino acid position 1827 to be replaced by a tyrosine (Y). 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
Benign
0.23
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
23
DANN
Uncertain
0.99
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.36
N
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.26
T;T
MetaSVM
Benign
-1.2
T
MutationTaster
Benign
0.90
D;D;D;D
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-4.0
D;D
REVEL
Benign
0.14
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.039
D;D
Vest4
0.35
MutPred
0.36
Gain of helix (P = 0.0225);.;
MVP
0.43
MPC
0.25
ClinPred
0.95
D
GERP RS
6.2
gMVP
0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-108380755; API