11-108509893-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015065.3(EXPH5):c.5614A>G(p.Thr1872Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,607,842 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (53 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.668

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021021366).
• BP6: Variant 11-108509893-T-C is Benign according to our data. Variant chr11-108509893-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 714777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00457 (696/152274) while in subpopulation NFE AF= 0.00345 (235/68030). AF 95% confidence interval is 0.00309. There are 5 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXPH5	NM_015065.3	c.5614A>G	p.Thr1872Ala	missense_variant	6/6	ENST00000265843.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXPH5	ENST00000265843.9	c.5614A>G	p.Thr1872Ala	missense_variant	6/6	1	NM_015065.3	P4
EXPH5	ENST00000525344.5	c.5593A>G	p.Thr1865Ala	missense_variant	7/7	1		A2

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 696 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00567 AC: 1388 AN: 244800 Hom.: 17 AF XY: 0.00580 AC XY: 767 AN XY: 132326

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000815

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000311

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.00479

Gnomad OTH exome AF: 0.00593

GnomAD4 exome AF: 0.00384 AC: 5588 AN: 1455568 Hom.: 53 Cov.: 33 AF XY: 0.00382 AC XY: 2766 AN XY: 723860

Gnomad4 AFR exome AF: 0.000423

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.0000777

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000683

Gnomad4 FIN exome AF: 0.0351

Gnomad4 NFE exome AF: 0.00309

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00457 AC: 696 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74466

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0411

Gnomad4 NFE AF: 0.00345

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00279 Hom.: 0

Bravo AF: 0.00175

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00557 AC: 676

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EXPH5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.37
Dann	Benign	0.23
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.041	N
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.012
Sift	Benign	0.37	T;T
Sift4G	Benign	0.79	T;T
Vest4		0.023
MVP		0.030
MPC		0.037
ClinPred		0.0061	T
GERP RS		-5.2
gMVP		0.11

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: rs143096226; hg19: chr11-108380620;