1-112649420-G-C

Variant names:

• chr1-112649420-G-C
• rs753793163
• NM_006135.3:c.106G>C

Variant summary

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

The NM_006135.3(CAPZA1):​c.106G>C​(p.Val36Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,052 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CAPZA1 NM_006135.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

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

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
CAPZA1	NM_006135.3	c.106G>C	p.Val36Leu	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000263168.4	NP_006126.1
CAPZA1	XM_017002424.3	c.106G>C	p.Val36Leu	missense_variant, splice_region_variant	Exon 3 of 10		XP_016857913.1
CAPZA1	XM_011542225.4	c.106G>C	p.Val36Leu	missense_variant, splice_region_variant	Exon 3 of 9		XP_011540527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPZA1	ENST00000263168.4	c.106G>C	p.Val36Leu	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_006135.3	ENSP00000263168.3
CAPZA1	ENST00000476936.5	n.132G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 8	3
CAPZA1	ENST00000485542.5	n.146G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	2
CAPZA1	ENST00000498626.1	n.159G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 9	5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74248

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.106G>C (p.V36L) alteration is located in exon 3 (coding exon 3) of the CAPZA1 gene. This alteration results from a G to C substitution at nucleotide position 106, causing the valine (V) at amino acid position 36 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	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.020
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.51
Sift	Benign	0.064	T
Sift4G	Benign	0.24	T
Polyphen		0.020	B
Vest4		0.76
MutPred		0.56		Gain of helix (P = 0.132);
MVP		0.77
MPC		0.30
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.60
gMVP		0.65

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: rs753793163; hg19: chr1-113192042; COSMIC: COSV99037013;