Genetic Variant CISD3:p.Arg16Gln (chr17-38730405-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001136498.2(CISD3):c.47G>A(p.Arg16Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 151,072 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CISD3
NM_001136498.2 missense, splice_region

Scores

Splicing: ADA: 0.001384

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06679121).

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>A	p.Arg16Gln	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>A	p.Arg16Gln	missense splice_region	Exon 1 of 4	ENSP00000483781.1	P0C7P0
CISD3	ENST00000619858.1	TSL:1	n.47G>A		non_coding_transcript_exon	Exon 1 of 3
CISD3	ENST00000894448.1		c.47G>A	p.Arg16Gln	missense splice_region	Exon 1 of 4	ENSP00000564507.1

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1066672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

504474

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:

0.00

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

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151072

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73762

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41296

American (AMR)

AF:

0.00

AC:

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67696

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.00052

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.21

M_CAP

Benign

0.0056

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.87

PrimateAI

Benign

0.46

Sift4G

Benign

0.29

Polyphen

0.029

Vest4

0.085

MutPred

0.22

Loss of MoRF binding (P = 0.0502)

MVP

0.014

ClinPred

0.076

GERP RS

1.0

PromoterAI

-0.083

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.13

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.12

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over