9-133468580-A-T

Position:

• chr9-133468580-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017586.5(CACFD1):​c.446A>T​(p.Tyr149Phe) 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 benign outcome for this variant. 11/19 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)
• Consequence: CACFD1 NM_017586.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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]

CACFD1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15489793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACFD1	NM_017586.5	c.446A>T	p.Tyr149Phe	missense_variant	5/5	ENST00000316948.9	NP_060056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACFD1	ENST00000316948.9	c.446A>T	p.Tyr149Phe	missense_variant	5/5	1	NM_017586.5	ENSP00000317121.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jan 19, 2024

The c.571A>T (p.M191L) alteration is located in exon 6 (coding exon 6) of the CACFD1 gene. This alteration results from a A to T substitution at nucleotide position 571, causing the methionine (M) at amino acid position 191 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	Benign	0.23
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.85
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.32	T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.95	D;D;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.19
Sift	Benign	0.15	T;T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.24
MutPred		0.19		.;Loss of methylation at R188 (P = 0.1201);
MVP		0.20
MPC		0.11
ClinPred		0.94	D
GERP RS		4.6
gMVP		0.056

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr9-136333702;