11-108510028-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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]

LOC112267909 (HGNC:):

ACMG classification

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	UniProt
EXPH5	NM_015065.3	c.5479G>T	p.Asp1827Tyr	missense_variant	6/6	ENST00000265843.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXPH5	ENST00000265843.9	c.5479G>T	p.Asp1827Tyr	missense_variant	6/6	1	NM_015065.3	P4
EXPH5	ENST00000525344.5	c.5458G>T	p.Asp1820Tyr	missense_variant	7/7	1		A2

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The 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;