12-6638956-T-C

Variant names:

• chr12-6638956-T-C
• NM_032489.3:c.1507A>G

Variant summary

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

The NM_032489.3(ACRBP):​c.1507A>G​(p.Lys503Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACRBP NM_032489.3 missense, splice_region
• Scores: Splicing: ADA: 0.1150
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

ACRBP (HGNC:17195): (acrosin binding protein) The protein encoded by this gene is similar to proacrosin binding protein sp32 precursor found in mouse, guinea pig, and pig. This protein is located in the sperm acrosome and is thought to function as a binding protein to proacrosin for packaging and condensation of the acrosin zymogen in the acrosomal matrix. This protein is a member of the cancer/testis family of antigens and it is found to be immunogenic. In normal tissues, this mRNA is expressed only in testis, whereas it is detected in a range of different tumor types such as bladder, breast, lung, liver, and colon. [provided by RefSeq, Jul 2008]

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 rank	MANE	Protein	UniProt
ACRBP	NM_032489.3	c.1507A>G	p.Lys503Glu	missense_variant, splice_region_variant	Exon 9 of 10	ENST00000229243.7	NP_115878.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACRBP	ENST00000229243.7	c.1507A>G	p.Lys503Glu	missense_variant, splice_region_variant	Exon 9 of 10	1	NM_032489.3	ENSP00000229243.2
ACRBP	ENST00000414226.6	c.1408A>G	p.Lys470Glu	missense_variant, splice_region_variant	Exon 9 of 10	2		ENSP00000402725.2
ACRBP	ENST00000542357.1	n.560A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 5	5
ACRBP	ENST00000540513.1	n.-105A>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1507A>G (p.K503E) alteration is located in exon 9 (coding exon 9) of the ACRBP gene. This alteration results from a A to G substitution at nucleotide position 1507, causing the lysine (K) at amino acid position 503 to be replaced by a glutamic acid (E). 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	0.28
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.50
MutPred		0.53		Gain of catalytic residue at M507 (P = 0);.;
MVP		0.50
MPC		0.72
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.28
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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: chr12-6748122;