11-108509797-A-G

Variant names:

• chr11-108509797-A-G
• rs1459391622
• NM_015065.3:c.5710T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015065.3(EXPH5):​c.5710T>C​(p.Ser1904Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EXPH5 NM_015065.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXPH5	NM_015065.3	c.5710T>C	p.Ser1904Pro	missense_variant	Exon 6 of 6	ENST00000265843.9	NP_055880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXPH5	ENST00000265843.9	c.5710T>C	p.Ser1904Pro	missense_variant	Exon 6 of 6	1	NM_015065.3	ENSP00000265843.4
EXPH5	ENST00000525344.5	c.5689T>C	p.Ser1897Pro	missense_variant	Exon 7 of 7	1		ENSP00000432546.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249932 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460402 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726494

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5710T>C (p.S1904P) alteration is located in exon 6 (coding exon 6) of the EXPH5 gene. This alteration results from a T to C substitution at nucleotide position 5710, causing the serine (S) at amino acid position 1904 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.44	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.76
MutPred		0.41		Gain of loop (P = 0.0013);.;
MVP		0.56
MPC		0.30
ClinPred		0.96	D
GERP RS		6.2
gMVP		0.65

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: rs1459391622; hg19: chr11-108380524;