Genetic Variant CISD3:p.Thr92Ile (chr17-38733346-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001136498.2(CISD3):c.275C>T(p.Thr92Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CISD3
NM_001136498.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.532

Variant links:

Genes affected

CISD3 (HGNC:27578): (CDGSH iron sulfur domain 3) CISD3 is a member of the CDGSH domain-containing family, which may play a role in regulating electron transport and oxidative phosphorylation (Wiley et al., 2007 [PubMed 17376863]).[supplied by OMIM, Apr 2008]

CISD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.26180637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CISD3	NM_001136498.2 link	c.275C>T	p.Thr92Ile	missense_variant	Exon 4 of 4	ENST00000613478.2	NP_001129970.1	P0C7P0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CISD3	ENST00000613478.2 link	c.275C>T	p.Thr92Ile	missense_variant	Exon 4 of 4	2	NM_001136498.2	ENSP00000483781.1	P0C7P0
CISD3	ENST00000619858.1 link	n.628C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1
CISD3	ENST00000616128.1 link	n.404C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000649

AC:

AN:

154058

Hom.:

AF XY:

0.00

AC XY:

AN XY:

81738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000917

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399368

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275C>T (p.T92I) alteration is located in exon 4 (coding exon 4) of the CISD3 gene. This alteration results from a C to T substitution at nucleotide position 275, causing the threonine (T) at amino acid position 92 to be replaced by an isoleucine (I). 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

0.77

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.40

M_CAP

Benign

0.014

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.9

PrimateAI

Uncertain

0.54

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.27

MutPred

0.55

Loss of disorder (P = 0.0183);

MVP

0.076

ClinPred

0.94

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over