11-108509712-G-T

Variant names:

• chr11-108509712-G-T
• rs150472827
• NM_015065.3:c.5795C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015065.3(EXPH5):​c.5795C>A​(p.Pro1932His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,457,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1932L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.834
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ENSG00000296559 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1515904).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015065.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXPH5	NM_015065.3	MANE Select	c.5795C>A	p.Pro1932His	missense	Exon 6 of 6	NP_055880.2	Q8NEV8-1
	EXPH5	NM_001441059.1		c.5792C>A	p.Pro1931His	missense	Exon 6 of 6	NP_001427988.1
	EXPH5	NM_001308019.2		c.5774C>A	p.Pro1925His	missense	Exon 7 of 7	NP_001294948.1	Q8NEV8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXPH5	ENST00000265843.9	TSL:1 MANE Select	c.5795C>A	p.Pro1932His	missense	Exon 6 of 6	ENSP00000265843.4	Q8NEV8-1
	EXPH5	ENST00000525344.5	TSL:1	c.5774C>A	p.Pro1925His	missense	Exon 7 of 7	ENSP00000432546.1	Q8NEV8-2
	ENSG00000296559	ENST00000740313.1		n.325-5599G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1457042 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724778

African (AFR) AF: 0.00 AC: 0 AN: 33118

American (AMR) AF: 0.00 AC: 0 AN: 43482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110648

Other (OTH) AF: 0.00 AC: 0 AN: 60136

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	-0.047
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.070	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.83
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.099
Sift	Benign	0.038	D
Sift4G	Benign	0.13	T
Vest4		0.092
MutPred		0.079		Loss of glycosylation at P1932 (P = 0.0395)
MVP		0.49
MPC		0.28
ClinPred		0.48	T
GERP RS		2.8
gMVP		0.13
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs150472827; hg19: chr11-108380439;