11-108509396-GA-GAA

Variant names:

• chr11-108509396-G-GA
• rs201174655
• NM_015065.3:c.*140dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_015065.3(EXPH5):​c.*140dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 706,684 control chromosomes in the GnomAD database, including 38 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (27 hom.)
• Consequence: EXPH5 NM_015065.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.774
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, Genomics England PanelApp

ENSG00000296559 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 11-108509396-G-GA is Benign according to our data. Variant chr11-108509396-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 2499330.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00577 (875/151704) while in subpopulation NFE AF = 0.00607 (412/67862). AF 95% confidence interval is 0.00559. There are 11 homozygotes in GnomAd4. There are 523 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.*140dupT		3_prime_UTR	Exon 6 of 6	NP_055880.2	Q8NEV8-1
	EXPH5	NM_001441059.1		c.*140dupT		3_prime_UTR	Exon 6 of 6	NP_001427988.1
	EXPH5	NM_001308019.2		c.*140dupT		3_prime_UTR	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.*140dupT		3_prime_UTR	Exon 6 of 6	ENSP00000265843.4	Q8NEV8-1
	EXPH5	ENST00000525344.5	TSL:1	c.*140dupT		3_prime_UTR	Exon 7 of 7	ENSP00000432546.1	Q8NEV8-2
	ENSG00000296559	ENST00000740313.1		n.325-5907dupA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 875 AN: 151586 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000896

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0391

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00241

GnomAD4 exome AF: 0.00603 AC: 3344 AN: 554980 Hom.: 27 Cov.: 8 AF XY: 0.00585 AC XY: 1680 AN XY: 287226

African (AFR) AF: 0.000746 AC: 11 AN: 14738

American (AMR) AF: 0.00155 AC: 30 AN: 19400

Ashkenazi Jewish (ASJ) AF: 0.000218 AC: 3 AN: 13742

East Asian (EAS) AF: 0.000123 AC: 4 AN: 32424

South Asian (SAS) AF: 0.000330 AC: 11 AN: 33342

European-Finnish (FIN) AF: 0.0298 AC: 959 AN: 32200

Middle Eastern (MID) AF: 0.000434 AC: 1 AN: 2302

European-Non Finnish (NFE) AF: 0.00576 AC: 2178 AN: 377852

Other (OTH) AF: 0.00507 AC: 147 AN: 28980

GnomAD4 genome AF: 0.00577 AC: 875 AN: 151704 Hom.: 11 Cov.: 32 AF XY: 0.00706 AC XY: 523 AN XY: 74110

African (AFR) AF: 0.000894 AC: 37 AN: 41408

American (AMR) AF: 0.000721 AC: 11 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.0391 AC: 408 AN: 10434

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

European-Non Finnish (NFE) AF: 0.00607 AC: 412 AN: 67862

Other (OTH) AF: 0.00238 AC: 5 AN: 2098

Alfa AF: 0.00502 Hom.: 1

Bravo AF: 0.00302

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.77
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: rs201174655; hg19: chr11-108380123;