7-99195159-C-A

Variant names:

• chr7-99195159-C-A
• rs115024192
• NM_001145715.3:c.464G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145715.3(KPNA7):​c.464G>T​(p.Gly155Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G155A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KPNA7 NM_001145715.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.130
• Publications: 0 publications found

Genes affected

KPNA7 (HGNC:21839): (karyopherin subunit alpha 7) The transport of molecules between the nucleus and the cytoplasm in eukaryotic cells is mediated by the nuclear pore complex (NPC), which consists of 60-100 proteins. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion while larger molecules are transported by an active process. The protein encoded by this gene belongs to the importin alpha family, and is involved in nuclear protein import, but exhibits different nuclear localization signal binding specificity compared to other members of the family. A pseudogene of this gene has been defined on chromosome 5. [provided by RefSeq, Jul 2016]

KPNA7 Gene-Disease associations (from GenCC):

• oocyte/zygote/embryo maturation arrest 17

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3890885).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145715.3. 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
	KPNA7	NM_001145715.3	MANE Select	c.464G>T	p.Gly155Val	missense	Exon 5 of 11	NP_001139187.1	A9QM74

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KPNA7	ENST00000327442.7	TSL:1 MANE Select	c.464G>T	p.Gly155Val	missense	Exon 5 of 11	ENSP00000330878.6	A9QM74
	KPNA7	ENST00000681060.1		c.464G>T	p.Gly155Val	missense	Exon 5 of 11	ENSP00000506489.1	A9QM74
	KPNA7	ENST00000893183.1		c.464G>T	p.Gly155Val	missense	Exon 5 of 11	ENSP00000563242.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399408 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690210

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078976

Other (OTH) AF: 0.00 AC: 0 AN: 58002

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.13
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.4	D
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.38
MutPred		0.46		Loss of disorder (P = 0.0604)
MVP		0.29
ClinPred		0.98	D
GERP RS		-0.29
Varity_R		0.22
gMVP		0.32
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs115024192; hg19: chr7-98792782;