11-108509878-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015065.3(EXPH5):c.5629G>T(p.Ala1877Ser) 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. 14/19 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: 0.227

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05614856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXPH5	NM_015065.3	c.5629G>T	p.Ala1877Ser	missense_variant	6/6	ENST00000265843.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXPH5	ENST00000265843.9	c.5629G>T	p.Ala1877Ser	missense_variant	6/6	1	NM_015065.3	P4
EXPH5	ENST00000525344.5	c.5608G>T	p.Ala1870Ser	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

May 08, 2023

The c.5629G>T (p.A1877S) 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 5629, causing the alanine (A) at amino acid position 1877 to be replaced by a serine (S). 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	0.091
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	14
Dann	Benign	0.92
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.086	N
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.038
Sift	Benign	0.16	T;T
Sift4G	Benign	0.66	T;T
Vest4		0.059
MutPred		0.29		Gain of phosphorylation at A1877 (P = 0.014);.;
MVP		0.072
MPC		0.048
ClinPred		0.064	T
GERP RS		-0.35
gMVP		0.12

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

Other links and lift over

dbSNP: rs2093665218; hg19: chr11-108380605;