rs56194394

Variant names:

• chr11-108509585-T-C
• rs56194394
• NM_015065.3:c.5922A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015065.3(EXPH5):​c.5922A>G​(p.Thr1974Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,592,320 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., cov: 32)
  • Exomes 𝑓: 0.016 (224 hom.)
• Consequence: EXPH5 NM_015065.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.54
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 11-108509585-T-C is Benign according to our data. Variant chr11-108509585-T-C is described in ClinVar as Benign. ClinVar VariationId is 1285243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1787/152362) while in subpopulation NFE AF = 0.0182 (1238/68044). AF 95% confidence interval is 0.0174. There are 15 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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.5922A>G	p.Thr1974Thr	synonymous	Exon 6 of 6	NP_055880.2	Q8NEV8-1
	EXPH5	NM_001441059.1		c.5919A>G	p.Thr1973Thr	synonymous	Exon 6 of 6	NP_001427988.1
	EXPH5	NM_001308019.2		c.5901A>G	p.Thr1967Thr	synonymous	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.5922A>G	p.Thr1974Thr	synonymous	Exon 6 of 6	ENSP00000265843.4	Q8NEV8-1
	EXPH5	ENST00000525344.5	TSL:1	c.5901A>G	p.Thr1967Thr	synonymous	Exon 7 of 7	ENSP00000432546.1	Q8NEV8-2
	ENSG00000296559	ENST00000740313.1		n.325-5726T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1787 AN: 152244 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0138 AC: 3183 AN: 229922 AF XY: 0.0142

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.00539

Gnomad ASJ exome AF: 0.00819

Gnomad EAS exome AF: 0.0000573

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0160 AC: 23064 AN: 1439958 Hom.: 224 Cov.: 32 AF XY: 0.0158 AC XY: 11322 AN XY: 715502

African (AFR) AF: 0.00312 AC: 101 AN: 32338

American (AMR) AF: 0.00537 AC: 212 AN: 39446

Ashkenazi Jewish (ASJ) AF: 0.00906 AC: 224 AN: 24712

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00360 AC: 292 AN: 81006

European-Finnish (FIN) AF: 0.0253 AC: 1335 AN: 52772

Middle Eastern (MID) AF: 0.0123 AC: 69 AN: 5628

European-Non Finnish (NFE) AF: 0.0181 AC: 19956 AN: 1104894

Other (OTH) AF: 0.0147 AC: 875 AN: 59524

GnomAD4 genome AF: 0.0117 AC: 1787 AN: 152362 Hom.: 15 Cov.: 32 AF XY: 0.0116 AC XY: 862 AN XY: 74508

African (AFR) AF: 0.00293 AC: 122 AN: 41582

American (AMR) AF: 0.00575 AC: 88 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4832

European-Finnish (FIN) AF: 0.0244 AC: 259 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1238 AN: 68044

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0171 Hom.: 39

Bravo AF: 0.0105

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.1
DANN	Benign	0.70
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs56194394; hg19: chr11-108380312;