Genetic Variant NM_172002.5:c.684C>G (chr22-28757145-C-G) – 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_172002.5(HSCB):c.684C>G(p.Ile228Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I228V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HSCB
NM_172002.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.426

Publications

0 publications found

Variant links:

Genes affected

HSCB (HGNC:28913): (HscB mitochondrial iron-sulfur cluster cochaperone) This gene encodes a DnaJ-type co-chaperone and member of the heat shock cognate B (HscB) family of proteins. The encoded protein plays a role in the synthesis of iron-sulfur clusters, protein cofactors that are involved in the redox reactions of mitochondrial electron transport and other processes. Cells in which this gene is knocked down exhibit reduced activity of iron-sulfur cluster-dependent enzymes including succinate dehydrogenase and aconitase. The encoded protein may stimulate the ATPase activity of the mitochondrial stress-70 protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

HSCB Gene-Disease associations (from GenCC):

anemia, sideroblastic, 5
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HSCB 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=0.26026803).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172002.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HSCB	NM_172002.5	MANE Select	c.684C>G	p.Ile228Met	missense	Exon 6 of 6	NP_741999.3
HSCB	NM_001318316.2		c.216C>G	p.Ile72Met	missense	Exon 6 of 6	NP_001305245.1
HSCB	NM_001318314.2		c.*86C>G		3_prime_UTR	Exon 5 of 5	NP_001305243.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSCB	ENST00000216027.8	TSL:1 MANE Select	c.684C>G	p.Ile228Met	missense	Exon 6 of 6	ENSP00000216027.3	Q8IWL3
HSCB	ENST00000913001.1		c.678C>G	p.Ile226Met	missense	Exon 6 of 6	ENSP00000583060.1
HSCB	ENST00000910455.1		c.657C>G	p.Ile219Met	missense	Exon 6 of 6	ENSP00000580514.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250366

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1402396

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700946

African (AFR)

AF:

0.00

AC:

AN:

32342

American (AMR)

AF:

0.00

AC:

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25666

East Asian (EAS)

AF:

0.00

AC:

AN:

39350

South Asian (SAS)

AF:

0.00

AC:

AN:

84902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1058834

Other (OTH)

AF:

0.00

AC:

AN:

58364

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.76

M_CAP

Benign

0.022

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.7

PhyloP100

0.43

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

REVEL

Benign

0.26

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.012

Polyphen

0.49

Vest4

0.44

MutPred

0.66

Gain of helix (P = 0.0128)

MVP

0.51

MPC

0.58

ClinPred

0.61

GERP RS

2.7

Varity_R

0.26

gMVP

0.44

Mutation Taster

=84/16

polymorphism

(source)

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

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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