chr1-112647213-C-A

Variant names:

• chr1-112647213-C-A
• rs763035612
• NM_006135.3:c.43C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006135.3(CAPZA1):​c.43C>A​(p.Arg15Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000736 in 1,358,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CAPZA1 NM_006135.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77
• Publications: 0 publications found

Genes affected

CAPZA1 (HGNC:1488): (capping actin protein of muscle Z-line subunit alpha 1) CAPZA1 is a member of the F-actin capping protein alpha subunit family. This gene encodes the alpha subunit of the barbed-end actin binding protein. The protein regulates growth of the actin filament by capping the barbed end of growing actin filaments. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006135.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPZA1	NM_006135.3	MANE Select	c.43C>A	p.Arg15Ser	missense	Exon 2 of 10	NP_006126.1	P52907

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPZA1	ENST00000263168.4	TSL:1 MANE Select	c.43C>A	p.Arg15Ser	missense	Exon 2 of 10	ENSP00000263168.3	P52907
	CAPZA1	ENST00000904626.1		c.43C>A	p.Arg15Ser	missense	Exon 2 of 10	ENSP00000574685.1
	CAPZA1	ENST00000917728.1		c.43C>A	p.Arg15Ser	missense	Exon 2 of 11	ENSP00000587787.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.36e-7 AC: 1 AN: 1358364 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 673926

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31056

American (AMR) AF: 0.00 AC: 0 AN: 38758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23828

East Asian (EAS) AF: 0.00 AC: 0 AN: 36976

South Asian (SAS) AF: 0.00 AC: 0 AN: 69540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5222

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1048050

Other (OTH) AF: 0.00 AC: 0 AN: 55322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0037	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.27
Sift	Uncertain	0.012	D
Sift4G	Benign	0.19	T
Polyphen		0.076	B
Vest4		0.81
MutPred		0.55		Gain of ubiquitination at K19 (P = 0.0483)
MVP		0.77
MPC		0.30
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.74
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs763035612; hg19: chr1-113189835;