11-108509988-G-T

Variant names:

• chr11-108509988-G-T
• rs190475331
• NM_015065.3:c.5519C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015065.3(EXPH5):​c.5519C>A​(p.Ser1840Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,902 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0568268).

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.5519C>A	p.Ser1840Tyr	missense	Exon 6 of 6	NP_055880.2	Q8NEV8-1
	EXPH5	NM_001441059.1		c.5516C>A	p.Ser1839Tyr	missense	Exon 6 of 6	NP_001427988.1
	EXPH5	NM_001308019.2		c.5498C>A	p.Ser1833Tyr	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.5519C>A	p.Ser1840Tyr	missense	Exon 6 of 6	ENSP00000265843.4	Q8NEV8-1
	EXPH5	ENST00000525344.5	TSL:1	c.5498C>A	p.Ser1833Tyr	missense	Exon 7 of 7	ENSP00000432546.1	Q8NEV8-2
	ENSG00000296559	ENST00000740313.1		n.325-5323G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000558 AC: 14 AN: 251042 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461564 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 727056

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000291 AC: 13 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111886

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	0.082
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.061
Sift	Benign	0.31	T
Sift4G	Benign	0.12	T
Vest4		0.24
MVP		0.38
MPC		0.28
ClinPred		0.17	T
GERP RS		4.3
gMVP		0.16
Mutation Taster		=92/8	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: rs190475331; hg19: chr11-108380715; COSMIC: COSV99762178; COSMIC: COSV99762178;