8-21990398-C-A

Variant names:

• chr8-21990398-C-A
• rs376605722
• NM_015024.5:c.1923C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015024.5(XPO7):​c.1923C>A​(p.Asn641Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: XPO7 NM_015024.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80
• Publications: 0 publications found

Genes affected

XPO7 (HGNC:14108): (exportin 7) The transport of protein and large RNAs through the nuclear pore complexes (NPC) is an energy-dependent and regulated process. The import of proteins with a nuclear localization signal (NLS) is accomplished by recognition of one or more clusters of basic amino acids by the importin-alpha/beta complex; see MIM 600685 and MIM 602738. The small GTPase RAN (MIM 601179) plays a key role in NLS-dependent protein import. RAN-binding protein-16 is a member of the importin-beta superfamily of nuclear transport receptors.[supplied by OMIM, Jul 2002]

XPO7 Gene-Disease associations (from GenCC):

• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2048442).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015024.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPO7	NM_015024.5	MANE Select	c.1923C>A	p.Asn641Lys	missense	Exon 17 of 28	NP_055839.3
	XPO7	NM_001100161.2		c.1950C>A	p.Asn650Lys	missense	Exon 17 of 28	NP_001093631.1
	XPO7	NM_001362802.2		c.1857C>A	p.Asn619Lys	missense	Exon 16 of 27	NP_001349731.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPO7	ENST00000252512.14	TSL:1 MANE Select	c.1923C>A	p.Asn641Lys	missense	Exon 17 of 28	ENSP00000252512.9	Q9UIA9
	XPO7	ENST00000433566.8	TSL:5	c.1926C>A	p.Asn642Lys	missense	Exon 17 of 28	ENSP00000410249.3	E7ESC6
	XPO7	ENST00000879832.1		c.1923C>A	p.Asn641Lys	missense	Exon 17 of 28	ENSP00000549891.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249242 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726978

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111688

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.092
Sift	Benign	0.48	T
Sift4G	Benign	0.91	T
Polyphen		0.0020	B
Vest4		0.47
MVP		0.068
MPC		0.58
ClinPred		0.34	T
GERP RS		5.2
Varity_R		0.47
gMVP		0.74
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs376605722; hg19: chr8-21847909;