chr12-48472869-C-A

Position:

• chr12-48472869-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012404.3(ANP32D):​c.205C>A​(p.Leu69Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANP32D NM_012404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

Genes affected

ANP32D (HGNC:16676): (acidic nuclear phosphoprotein 32 family member D) Phosphoprotein 32 (PP32) is a tumor suppressor that can inhibit several types of cancers, including prostate and breast cancers. The protein encoded by this gene is one of at least two proteins that are similar in amino acid sequence to PP32 and are part of the same acidic nuclear phosphoprotein gene family. However, unlike PP32, the encoded protein is tumorigenic. The tumor suppressor function of PP32 has been localized to a 25 amino acid region that is absent in the protein encoded by this gene. This gene does not contain introns. [provided by RefSeq, Jul 2008]

C12orf54 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36382455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANP32D	NM_012404.3	c.205C>A	p.Leu69Ile	missense_variant	1/1	ENST00000266594.4	NP_036536.2
C12orf54	XM_011537896.3	c.-19-13309C>A		intron_variant			XP_011536198.1
C12orf54	XM_017018796.2	c.-93-1109C>A		intron_variant			XP_016874285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANP32D	ENST00000266594.4	c.205C>A	p.Leu69Ile	missense_variant	1/1		NM_012404.3	ENSP00000266594	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727204

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 09, 2023

The c.205C>A (p.L69I) alteration is located in exon 1 (coding exon 1) of the ANP32D gene. This alteration results from a C to A substitution at nucleotide position 205, causing the leucine (L) at amino acid position 69 to be replaced by an isoleucine (I). 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	0.18
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.0035
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.0083	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.54		Gain of sheet (P = 0.0827);
MVP		0.56
MPC		0.0074
ClinPred		0.99	D
GERP RS		-0.68
Varity_R		0.63
gMVP		0.58

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: rs1954090967; hg19: chr12-48866652;