11-108509585-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015065.3(EXPH5):c.5922A>G(p.Thr1974=) 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:2
• Conservation: PhyloP100: -1.54

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXPH5	NM_015065.3	c.5922A>G	p.Thr1974=	synonymous_variant	6/6	ENST00000265843.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXPH5	ENST00000265843.9	c.5922A>G	p.Thr1974=	synonymous_variant	6/6	1	NM_015065.3	P4
EXPH5	ENST00000525344.5	c.5901A>G	p.Thr1967=	synonymous_variant	7/7	1		A2

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

GnomAD3 exomes AF: 0.0138 AC: 3183 AN: 229922 Hom.: 31 AF XY: 0.0142 AC XY: 1756 AN XY: 123864

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 SAS exome AF: 0.00420

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

Gnomad4 AFR exome AF: 0.00312

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.00906

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00360

Gnomad4 FIN exome AF: 0.0253

Gnomad4 NFE exome AF: 0.0181

Gnomad4 OTH exome AF: 0.0147

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

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0244

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0161 Hom.: 15

Bravo AF: 0.0105

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.1
Dann	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs56194394; hg19: chr11-108380312;