7-99188376-C-G

Variant names:

• chr7-99188376-C-G
• rs377664445
• NM_001145715.3:c.824G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001145715.3(KPNA7):​c.824G>C​(p.Arg275Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KPNA7 NM_001145715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

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.824G>C	p.Arg275Pro	missense	Exon 7 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.824G>C	p.Arg275Pro	missense	Exon 7 of 11	ENSP00000330878.6	A9QM74
	KPNA7	ENST00000681060.1		c.824G>C	p.Arg275Pro	missense	Exon 7 of 11	ENSP00000506489.1	A9QM74
	KPNA7	ENST00000893183.1		c.824G>C	p.Arg275Pro	missense	Exon 7 of 11	ENSP00000563242.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.055	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		3.3
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.52		Loss of MoRF binding (P = 0.0768)
MVP		0.35
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.87
gMVP		0.86
Mutation Taster		=56/44	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: rs377664445; hg19: chr7-98785999;