15-68787920-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_006305.4(ANP32A):​c.55-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ANP32A
NM_006305.4 splice_acceptor, intron

Scores

3
3
1
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.81
Variant links:
Genes affected
ANP32A (HGNC:13233): (acidic nuclear phosphoprotein 32 family member A) Enables RNA binding activity. Involved in nucleocytoplasmic transport. Located in endoplasmic reticulum; nucleus; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of -43, new splice context is: acaccctccccctgcttcAGccc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANP32ANM_006305.4 linkc.55-1G>C splice_acceptor_variant, intron_variant Intron 1 of 6 ENST00000465139.6 NP_006296.1 P39687A0A384P5U2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANP32AENST00000465139.6 linkc.55-1G>C splice_acceptor_variant, intron_variant Intron 1 of 6 1 NM_006305.4 ENSP00000417864.2 P39687

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jan 10, 2022
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Gene of Uncertain Significance -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.96
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.76
Position offset: 42
DS_AL_spliceai
0.99
Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-69080259; API