Genetic Variant CISD3:p.Arg16Leu (chr17-38730405-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001136498.2(CISD3):c.47G>T(p.Arg16Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000937 in 1,066,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.4e-7 ( 0 hom. )

Consequence

CISD3
NM_001136498.2 missense, splice_region

Scores

Splicing: ADA: 0.002350

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.868

Publications

3 publications found

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:

ENSG00000275665 (HGNC:):

ENSG00000275665 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07086456).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136498.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISD3	NM_001136498.2	MANE Select	c.47G>T	p.Arg16Leu	missense splice_region	Exon 1 of 4	NP_001129970.1	P0C7P0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CISD3	ENST00000613478.2	TSL:2 MANE Select	c.47G>T	p.Arg16Leu	missense splice_region	Exon 1 of 4	ENSP00000483781.1	P0C7P0
CISD3	ENST00000619858.1	TSL:1	n.47G>T		non_coding_transcript_exon	Exon 1 of 3
CISD3	ENST00000894448.1		c.47G>T	p.Arg16Leu	missense splice_region	Exon 1 of 4	ENSP00000564507.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.37e-7

AC:

AN:

1066672

Hom.:

Cov.:

AF XY:

0.00000198

AC XY:

AN XY:

504474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22188

American (AMR)

AF:

0.00

AC:

AN:

7802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13682

East Asian (EAS)

AF:

0.0000397

AC:

AN:

25164

South Asian (SAS)

AF:

0.00

AC:

AN:

21280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2872

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

910062

Other (OTH)

AF:

0.00

AC:

AN:

42592

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.00098

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.18

M_CAP

Benign

0.0066

MetaRNN

Benign

0.071

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.87

PrimateAI

Benign

0.48

Sift4G

Benign

0.16

Polyphen

0.0

Vest4

0.10

MutPred

0.27

Loss of disorder (P = 0.0244)

MVP

0.14

ClinPred

0.058

GERP RS

1.0

PromoterAI

0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.32

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0024

dbscSNV1_RF

Benign

0.020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over