chr1-112654603-T-C

Position:

• chr1-112654603-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006135.3(CAPZA1):​c.358T>C​(p.Trp120Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPZA1 NM_006135.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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]

CAPZA1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPZA1	NM_006135.3	c.358T>C	p.Trp120Arg	missense_variant	5/10	ENST00000263168.4	NP_006126.1
CAPZA1	XM_017002424.3	c.358T>C	p.Trp120Arg	missense_variant	5/10		XP_016857913.1
CAPZA1	XM_011542225.4	c.358T>C	p.Trp120Arg	missense_variant	5/9		XP_011540527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPZA1	ENST00000263168.4	c.358T>C	p.Trp120Arg	missense_variant	5/10	1	NM_006135.3	ENSP00000263168.3
CAPZA1	ENST00000498626.1	n.411T>C		non_coding_transcript_exon_variant	6/9	5
CAPZA1	ENST00000476936.5	n.182-4419T>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2024

The c.358T>C (p.W120R) alteration is located in exon 5 (coding exon 5) of the CAPZA1 gene. This alteration results from a T to C substitution at nucleotide position 358, causing the tryptophan (W) at amino acid position 120 to be replaced by an arginine (R). 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	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-9.8	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.039	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.84		Gain of disorder (P = 0.0073);
MVP		0.74
MPC		0.81
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-113197225;