11-108510054-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_015065.3(EXPH5):c.5453G>A(p.Arg1818His) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,610,726 control chromosomes in the GnomAD database, including 1 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 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.63

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]

LOC112267909 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010061085).
• BP6: Variant 11-108510054-C-T is Benign according to our data. Variant chr11-108510054-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 730959.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000171 (26/152258) while in subpopulation AMR AF= 0.00124 (19/15294). AF 95% confidence interval is 0.000813. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXPH5	NM_015065.3	c.5453G>A	p.Arg1818His	missense_variant	6/6	ENST00000265843.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXPH5	ENST00000265843.9	c.5453G>A	p.Arg1818His	missense_variant	6/6	1	NM_015065.3	P4
EXPH5	ENST00000525344.5	c.5432G>A	p.Arg1811His	missense_variant	7/7	1		A2
EXPH5	ENST00000526312.5			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000598 AC: 148 AN: 247436 Hom.: 1 AF XY: 0.000396 AC XY: 53 AN XY: 133794

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00424

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 189 AN: 1458468 Hom.: 1 Cov.: 33 AF XY: 0.000102 AC XY: 74 AN XY: 725470

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74434

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000681 Hom.: 0

Bravo AF: 0.000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.5453G>A (p.R1818H) alteration is located in exon 6 (coding exon 6) of the EXPH5 gene. This alteration results from a G to A substitution at nucleotide position 5453, causing the arginine (R) at amino acid position 1818 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.012	D;D
Vest4		0.68
MVP		0.44
MPC		0.30
ClinPred		0.088	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs201149792; hg19: chr11-108380781; COSMIC: COSV56199873; COSMIC: COSV56199873;