15-68780086-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006305.4(ANP32A):c.745G>A(p.Asp249Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ANP32A NM_006305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ANP32A
• BP4: Computational evidence support a benign effect (MetaRNN=0.16083321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANP32A	NM_006305.4	c.745G>A	p.Asp249Asn	missense_variant	7/7	ENST00000465139.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANP32A	ENST00000465139.6	c.745G>A	p.Asp249Asn	missense_variant	7/7	1	NM_006305.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461392 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726998

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.745G>A (p.D249N) alteration is located in exon 7 (coding exon 7) of the ANP32A gene. This alteration results from a G to A substitution at nucleotide position 745, causing the aspartic acid (D) at amino acid position 249 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.048
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.088
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.19	T
Polyphen		0.023	B
Vest4		0.37
MutPred		0.23		Gain of helix (P = 0.2684);
MVP		0.37
MPC		1.1
ClinPred		0.94	D
GERP RS		4.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.35
gMVP		0.0041

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

Publications

LitVar

Other links and lift over

dbSNP: rs1347646398; hg19: chr15-69072425;