11-108509902-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_015065.3(EXPH5):c.5605G>A(p.Gly1869Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000871 in 1,606,678 control chromosomes in the GnomAD database, including 1 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (1 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.645

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0076721013).
• BP6: Variant 11-108509902-C-T is Benign according to our data. Variant chr11-108509902-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3091267.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000243 (37/152204) while in subpopulation AFR AF= 0.000698 (29/41526). AF 95% confidence interval is 0.000499. There are 0 homozygotes in gnomad4. There are 16 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.5605G>A	p.Gly1869Arg	missense_variant	6/6	ENST00000265843.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXPH5	ENST00000265843.9	c.5605G>A	p.Gly1869Arg	missense_variant	6/6	1	NM_015065.3	P4
EXPH5	ENST00000525344.5	c.5584G>A	p.Gly1862Arg	missense_variant	7/7	1		A2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 27 AN: 244058 Hom.: 0 AF XY: 0.0000985 AC XY: 13 AN XY: 131936

Gnomad AFR exome AF: 0.000682

Gnomad AMR exome AF: 0.0000604

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000539

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.0000708 AC: 103 AN: 1454474 Hom.: 1 Cov.: 33 AF XY: 0.0000830 AC XY: 60 AN XY: 723322

Gnomad4 AFR exome AF: 0.000696

Gnomad4 AMR exome AF: 0.0000927

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000260

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000370

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74410

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.068
Dann	Benign	0.17
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0032	N
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	2.5	N;N
REVEL	Benign	0.032
Sift	Benign	1.0	T;T
Sift4G	Benign	0.79	T;T
Vest4		0.053
MutPred		0.19		Loss of ubiquitination at K1871 (P = 0.0224);.;
MVP		0.040
MPC		0.041
ClinPred		0.0031	T
GERP RS		-0.87
gMVP		0.061

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: rs181581015; hg19: chr11-108380629; COSMIC: COSV99761069; COSMIC: COSV99761069;