11-108509554-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_015065.3(EXPH5):c.5953A>G(p.Lys1985Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00509 in 1,556,862 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (35 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.83

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 -10 ACMG points.

• BP6: Variant 11-108509554-T-C is Benign according to our data. Variant chr11-108509554-T-C is described in ClinVar as [Benign]. Clinvar id is 719499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-108509554-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00286 (435/152342) while in subpopulation NFE AF= 0.00506 (344/68022). AF 95% confidence interval is 0.00462. There are 1 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXPH5	NM_015065.3	c.5953A>G	p.Lys1985Glu	missense_variant	6/6	ENST00000265843.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXPH5	ENST00000265843.9	c.5953A>G	p.Lys1985Glu	missense_variant	6/6	1	NM_015065.3	P4
EXPH5	ENST00000525344.5	c.5932A>G	p.Lys1978Glu	missense_variant	7/7	1		A2

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00506

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00270 AC: 538 AN: 199500 Hom.: 2 AF XY: 0.00259 AC XY: 277 AN XY: 106908

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00198

Gnomad NFE exome AF: 0.00481

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.00533 AC: 7482 AN: 1404520 Hom.: 35 Cov.: 31 AF XY: 0.00516 AC XY: 3587 AN XY: 695222

Gnomad4 AFR exome AF: 0.000743

Gnomad4 AMR exome AF: 0.000315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.00664

Gnomad4 OTH exome AF: 0.00226

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00267 AC XY: 199 AN XY: 74510

Gnomad4 AFR AF: 0.000697

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00506

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00414 Hom.: 2

Bravo AF: 0.00289

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00246 AC: 298

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Uncertain	-0.11	T
MutationTaster	Benign	0.83	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0090	D;D
Vest4		0.33
MVP		0.66
MPC		0.27
ClinPred		0.029	T
GERP RS		5.8
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146199863; hg19: chr11-108380281; COSMIC: COSV104554172; COSMIC: COSV104554172;