12-18738524-C-G

Variant names:

• chr12-18738524-C-G
• rs777481523
• NM_033328.3:c.256C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.202

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]

ACMG classification

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
CAPZA3	NM_033328.3	c.256C>G	p.His86Asp	missense_variant	Exon 1 of 1	ENST00000317658.5	NP_201585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPZA3	ENST00000317658.5	c.256C>G	p.His86Asp	missense_variant	Exon 1 of 1	6	NM_033328.3	ENSP00000326238.3

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

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

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

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

Other links and lift over

dbSNP: rs777481523; hg19: chr12-18891458;