chr7-99173752-G-A

Position:

• chr7-99173752-G-A

Variant summary

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

The NM_001145715.3(KPNA7):​c.1507C>T​(p.Gln503Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,399,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KPNA7 NM_001145715.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00700

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]

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/exons	MANE	Protein	UniProt
KPNA7	NM_001145715.3	c.1507C>T	p.Gln503Ter	stop_gained	11/11	ENST00000327442.7	NP_001139187.1
KPNA7	XM_011516215.3	c.1588C>T	p.Gln530Ter	stop_gained	11/11		XP_011514517.1
KPNA7	XM_017012211.2	c.1545+4168C>T		intron_variant			XP_016867700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KPNA7	ENST00000327442.7	c.1507C>T	p.Gln503Ter	stop_gained	11/11	1	NM_001145715.3	ENSP00000330878	P1
KPNA7	ENST00000681060.1	c.1507C>T	p.Gln503Ter	stop_gained	11/11			ENSP00000506489	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000164 AC: 23 AN: 1399418 Hom.: 0 Cov.: 29 AF XY: 0.0000145 AC XY: 10 AN XY: 690188

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: 0.0000204

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 16, 2021

This sequence change results in a premature translational stop signal in the KPNA7 gene (p.Gln503*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acids of the KPNA7 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KPNA7-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Benign	0.80
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.11	N
MutationTaster	Benign	1.0	D
Vest4		0.094
GERP RS		-6.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs774947420; hg19: chr7-98771375;