12-6638314-A-G

Variant names:

• chr12-6638314-A-G
• rs1592305178
• NM_032489.3:c.1600T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032489.3(ACRBP):​c.1600T>C​(p.Phe534Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ACRBP NM_032489.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACRBP	NM_032489.3	c.1600T>C	p.Phe534Leu	missense_variant	Exon 10 of 10	ENST00000229243.7	NP_115878.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACRBP	ENST00000229243.7	c.1600T>C	p.Phe534Leu	missense_variant	Exon 10 of 10	1	NM_032489.3	ENSP00000229243.2
ACRBP	ENST00000540513.1	n.268T>C		non_coding_transcript_exon_variant	Exon 2 of 2	1
ACRBP	ENST00000414226.6	c.1501T>C	p.Phe501Leu	missense_variant	Exon 10 of 10	2		ENSP00000402725.2
ACRBP	ENST00000542357.1	n.*196T>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1600T>C (p.F534L) alteration is located in exon 10 (coding exon 10) of the ACRBP gene. This alteration results from a T to C substitution at nucleotide position 1600, causing the phenylalanine (F) at amino acid position 534 to be replaced by a leucine (L). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.76
MutPred		0.69		Gain of catalytic residue at T536 (P = 0.0412);.;
MVP		0.71
MPC		1.1
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.84

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: rs1592305178; hg19: chr12-6747480;