11-108509893-T-C

Variant names:

• chr11-108509893-T-C
• rs143096226
• NM_015065.3:c.5614A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015065.3(EXPH5):​c.5614A>G​(p.Thr1872Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,607,842 control chromosomes in the GnomAD database, including 58 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (53 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.668
• Publications: 5 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021021366).
• BP6: Variant 11-108509893-T-C is Benign according to our data. Variant chr11-108509893-T-C is described in ClinVar as Benign. ClinVar VariationId is 714777.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00457 (696/152274) while in subpopulation NFE AF = 0.00345 (235/68030). AF 95% confidence interval is 0.00309. There are 5 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.5614A>G	p.Thr1872Ala	missense	Exon 6 of 6	NP_055880.2	Q8NEV8-1
	EXPH5	NM_001441059.1		c.5611A>G	p.Thr1871Ala	missense	Exon 6 of 6	NP_001427988.1
	EXPH5	NM_001308019.2		c.5593A>G	p.Thr1865Ala	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.5614A>G	p.Thr1872Ala	missense	Exon 6 of 6	ENSP00000265843.4	Q8NEV8-1
	EXPH5	ENST00000525344.5	TSL:1	c.5593A>G	p.Thr1865Ala	missense	Exon 7 of 7	ENSP00000432546.1	Q8NEV8-2
	ENSG00000296559	ENST00000740313.1		n.325-5418T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 696 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00567 AC: 1388 AN: 244800 AF XY: 0.00580

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000815

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.00479

Gnomad OTH exome AF: 0.00593

GnomAD4 exome AF: 0.00384 AC: 5588 AN: 1455568 Hom.: 53 Cov.: 33 AF XY: 0.00382 AC XY: 2766 AN XY: 723860

African (AFR) AF: 0.000423 AC: 14 AN: 33086

American (AMR) AF: 0.000715 AC: 31 AN: 43378

Ashkenazi Jewish (ASJ) AF: 0.0000777 AC: 2 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000683 AC: 58 AN: 84862

European-Finnish (FIN) AF: 0.0351 AC: 1872 AN: 53270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00309 AC: 3433 AN: 1109802

Other (OTH) AF: 0.00296 AC: 178 AN: 60078

GnomAD4 genome AF: 0.00457 AC: 696 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74466

African (AFR) AF: 0.000361 AC: 15 AN: 41554

American (AMR) AF: 0.000196 AC: 3 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.0411 AC: 436 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00345 AC: 235 AN: 68030

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00308 Hom.: 3

Bravo AF: 0.00175

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00557 AC: 676

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	EXPH5-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.37
DANN	Benign	0.23
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.041	N
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.90	T
PhyloP100		-0.67
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.012
Sift	Benign	0.37	T
Sift4G	Benign	0.79	T
Vest4		0.023
MVP		0.030
MPC		0.037
ClinPred		0.0061	T
GERP RS		-5.2
gMVP		0.11
Mutation Taster		=100/0	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: rs143096226; hg19: chr11-108380620;