rs770136434

Variant names:

• chr22-28751249-A-C
• rs770136434
• NM_172002.5:c.577A>C

Your query was ambiguous. Multiple possible variants found:

• chr22-28751249-A-C
• chr22-28751249-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172002.5(HSCB):​c.577A>C​(p.Lys193Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. K193E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HSCB NM_172002.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 1 publications found

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)

ACMG classification

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=0.12408227).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSCB	NM_172002.5	MANE Select	c.577A>C	p.Lys193Gln	missense	Exon 5 of 6	NP_741999.3
	HSCB	NM_001318314.2		c.432A>C	p.Arg144Ser	missense	Exon 4 of 5	NP_001305243.1
	HSCB	NM_001318316.2		c.109A>C	p.Lys37Gln	missense	Exon 5 of 6	NP_001305245.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSCB	ENST00000216027.8	TSL:1 MANE Select	c.577A>C	p.Lys193Gln	missense	Exon 5 of 6	ENSP00000216027.3	Q8IWL3
	HSCB	ENST00000913001.1		c.571A>C	p.Lys191Gln	missense	Exon 5 of 6	ENSP00000583060.1
	HSCB	ENST00000910455.1		c.550A>C	p.Lys184Gln	missense	Exon 5 of 6	ENSP00000580514.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445172 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 718978

African (AFR) AF: 0.0000302 AC: 1 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 43556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 83800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100646

Other (OTH) AF: 0.00 AC: 0 AN: 59814

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.14
Sift	Benign	0.31	T
Sift4G	Benign	0.52	T
Polyphen		0.0040	B
Vest4		0.26
MutPred		0.46		Loss of ubiquitination at K193 (P = 0.0081)
MVP		0.59
MPC		0.18
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.32
gMVP		0.18
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770136434; hg19: chr22-29147237;