12-18738524-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033328.3(CAPZA3):​c.256C>G​(p.His86Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CAPZA3
NM_033328.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.202
Variant links:
Genes affected
CAPZA3 (HGNC:24205): (capping actin protein of muscle Z-line subunit alpha 3) This gene encodes an actin capping protein, one of the F-actin capping protein alpha subunit family. The encoded protein is predominantly localized to the neck region of ejaculated sperm, other immunohistochemical signals were found in the tail and postacrosomal regions. The encoded protein may also form heterodimers of alpha and beta subunits. This protein may be important in determining sperm architecture and male fertility. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.033469617).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CAPZA3NM_033328.3 linkc.256C>G p.His86Asp missense_variant Exon 1 of 1 ENST00000317658.5 NP_201585.1 Q96KX2A0A140VKF6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CAPZA3ENST00000317658.5 linkc.256C>G p.His86Asp missense_variant Exon 1 of 1 6 NM_033328.3 ENSP00000326238.3 Q96KX2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.000112
AC:
28
AN:
250992
Hom.:
0
AF XY:
0.0000885
AC XY:
12
AN XY:
135616
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000811
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461816
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
13
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000671
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000189
ExAC
AF:
0.0000988
AC:
12

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 20, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.256C>G (p.H86D) alteration is located in exon 1 (coding exon 1) of the CAPZA3 gene. This alteration results from a C to G substitution at nucleotide position 256, causing the histidine (H) at amino acid position 86 to be replaced by an aspartic acid (D). 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
0.17
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
12
DANN
Benign
0.89
DEOGEN2
Benign
0.052
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.0039
T
MetaRNN
Benign
0.033
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
0.36
N
REVEL
Benign
0.047
Sift
Benign
0.081
T
Sift4G
Benign
0.38
T
Polyphen
0.0050
B
Vest4
0.30
MutPred
0.55
Gain of ubiquitination at K89 (P = 0.0762);
MVP
0.17
MPC
0.036
ClinPred
0.021
T
GERP RS
-1.0
Varity_R
0.063
gMVP
0.59

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs777481523; hg19: chr12-18891458; API