rs776949863

Variant names:

• chr11-108509770-G-T
• rs776949863
• NM_015065.3:c.5737C>A

Variant summary

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

The NM_015065.3(EXPH5):​c.5737C>A​(p.Pro1913Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,607,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27
• Publications: 1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, Genomics England PanelApp

ENSG00000296559 (HGNC:):

ACMG classification

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

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.5737C>A	p.Pro1913Thr	missense	Exon 6 of 6	NP_055880.2	Q8NEV8-1
	EXPH5	NM_001441059.1		c.5734C>A	p.Pro1912Thr	missense	Exon 6 of 6	NP_001427988.1
	EXPH5	NM_001308019.2		c.5716C>A	p.Pro1906Thr	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.5737C>A	p.Pro1913Thr	missense	Exon 6 of 6	ENSP00000265843.4	Q8NEV8-1
	EXPH5	ENST00000525344.5	TSL:1	c.5716C>A	p.Pro1906Thr	missense	Exon 7 of 7	ENSP00000432546.1	Q8NEV8-2
	ENSG00000296559	ENST00000740313.1		n.325-5541G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000696 AC: 17 AN: 244404 AF XY: 0.0000983

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000563 AC: 82 AN: 1455538 Hom.: 0 Cov.: 32 AF XY: 0.0000566 AC XY: 41 AN XY: 724008

African (AFR) AF: 0.0000303 AC: 1 AN: 32950

American (AMR) AF: 0.00 AC: 0 AN: 42956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000707 AC: 6 AN: 84878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.000877 AC: 5 AN: 5704

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1110322

Other (OTH) AF: 0.0000666 AC: 4 AN: 60036

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74450

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000906 AC: 11

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.85
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.36	T
PhyloP100		7.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Vest4		0.73
MutPred		0.49		Loss of loop (P = 0.0374)
MVP		0.60
MPC		0.29
ClinPred		0.50	D
GERP RS		6.0
gMVP		0.36
Mutation Taster		=66/34	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: rs776949863; hg19: chr11-108380497;