rs146199863

Variant names:

• chr11-108509554-T-C
• rs146199863
• NM_015065.3:c.5953A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_015065.3(EXPH5):​c.5953A>G​(p.Lys1985Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00509 in 1,556,862 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (35 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.83
• Publications: 12 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 11-108509554-T-C is Benign according to our data. Variant chr11-108509554-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 719499.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00286 (435/152342) while in subpopulation NFE AF = 0.00506 (344/68022). AF 95% confidence interval is 0.00462. There are 1 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 35 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.5953A>G	p.Lys1985Glu	missense	Exon 6 of 6	NP_055880.2	Q8NEV8-1
	EXPH5	NM_001441059.1		c.5950A>G	p.Lys1984Glu	missense	Exon 6 of 6	NP_001427988.1
	EXPH5	NM_001308019.2		c.5932A>G	p.Lys1978Glu	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.5953A>G	p.Lys1985Glu	missense	Exon 6 of 6	ENSP00000265843.4	Q8NEV8-1
	EXPH5	ENST00000525344.5	TSL:1	c.5932A>G	p.Lys1978Glu	missense	Exon 7 of 7	ENSP00000432546.1	Q8NEV8-2
	ENSG00000296559	ENST00000740313.1		n.325-5757T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00270 AC: 538 AN: 199500 AF XY: 0.00259

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00198

Gnomad NFE exome AF: 0.00481

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.00533 AC: 7482 AN: 1404520 Hom.: 35 Cov.: 31 AF XY: 0.00516 AC XY: 3587 AN XY: 695222

African (AFR) AF: 0.000743 AC: 23 AN: 30948

American (AMR) AF: 0.000315 AC: 10 AN: 31770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22038

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 74940

European-Finnish (FIN) AF: 0.00156 AC: 80 AN: 51342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5452

European-Non Finnish (NFE) AF: 0.00664 AC: 7237 AN: 1090668

Other (OTH) AF: 0.00226 AC: 131 AN: 57926

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74510

African (AFR) AF: 0.000697 AC: 29 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00506 AC: 344 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00407 Hom.: 4

Bravo AF: 0.00289

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00246 AC: 298

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0088	T
MetaSVM	Uncertain	-0.11	T
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Vest4		0.33
MVP		0.66
MPC		0.27
ClinPred		0.029	T
GERP RS		5.8
gMVP		0.16
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146199863; hg19: chr11-108380281; COSMIC: COSV104554172; COSMIC: COSV104554172;