10-58277132-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018464.5(CISD1):c.47C>T(p.Ala16Val) variant causes a missense change. 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: 31)
• Consequence: CISD1 NM_018464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60

Genes affected

CISD1 (HGNC:30880): (CDGSH iron sulfur domain 1) This gene encodes a protein with a CDGSH iron-sulfur domain and has been shown to bind a redox-active [2Fe-2S] cluster. The encoded protein has been localized to the outer membrane of mitochondria and is thought to play a role in regulation of oxidation. Genes encoding similar proteins are located on chromosomes 4 and 17, and a pseudogene of this gene is located on chromosome 2. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CISD1	NM_018464.5	c.47C>T	p.Ala16Val	missense_variant	2/3	ENST00000333926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CISD1	ENST00000333926.6	c.47C>T	p.Ala16Val	missense_variant	2/3	1	NM_018464.5	P1
CISD1	ENST00000464703.5	n.238C>T		non_coding_transcript_exon_variant	3/5	5
CISD1	ENST00000488388.2	n.68C>T		non_coding_transcript_exon_variant	2/4	5
CISD1	ENST00000489785.5	n.115C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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 08, 2024

The c.47C>T (p.A16V) alteration is located in exon 2 (coding exon 2) of the CISD1 gene. This alteration results from a C to T substitution at nucleotide position 47, causing the alanine (A) at amino acid position 16 to be replaced by a valine (V). 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	0.25
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.22
Sift	Benign	0.67	T
Sift4G	Benign	0.28	T
Polyphen		0.95	P
Vest4		0.64
MutPred		0.58		Gain of sheet (P = 0.0149);
MVP		0.54
MPC		0.90
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.11
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: rs1253483789; hg19: chr10-60036892;