9-133463489-C-A

Variant names:

• chr9-133463489-C-A
• NM_017586.5:c.128C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017586.5(CACFD1):​c.128C>A​(p.Ala43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACFD1 NM_017586.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

Genes affected

CACFD1 (HGNC:1365): (calcium channel flower domain containing 1) Predicted to be involved in vesicle-mediated transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACFD1	NM_017586.5	c.128C>A	p.Ala43Glu	missense_variant	Exon 2 of 5	ENST00000316948.9	NP_060056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACFD1	ENST00000316948.9	c.128C>A	p.Ala43Glu	missense_variant	Exon 2 of 5	1	NM_017586.5	ENSP00000317121.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.128C>A (p.A43E) alteration is located in exon 2 (coding exon 2) of the CACFD1 gene. This alteration results from a C to A substitution at nucleotide position 128, causing the alanine (A) at amino acid position 43 to be replaced by a glutamic acid (E). 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	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	.;.;.;T;.
Eigen	Benign	0.043
Eigen_PC	Benign	0.0048
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;D;T;D;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.1	M;M;M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D;D;D;D;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D;T;D;T;D
Sift4G	Benign	0.067	T;T;T;T;D
Polyphen		1.0, 0.54	.;.;D;P;.
Vest4		0.82
MutPred		0.71		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);.;
MVP		0.61
MPC		0.38
ClinPred		0.94	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-136328611;