chr22-28749551-C-T

Variant names:

• chr22-28749551-C-T
• rs5997391
• NM_172002.5:c.569-1690C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172002.5(HSCB):​c.569-1690C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0702 in 152,218 control chromosomes in the GnomAD database, including 454 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.070 (454 hom., cov: 31)
• Consequence: HSCB NM_172002.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.388
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSCB	NM_172002.5	MANE Select	c.569-1690C>T		intron	N/A	NP_741999.3
	HSCB	NM_001318314.2		c.424-1690C>T		intron	N/A	NP_001305243.1
	HSCB	NM_001318315.2		c.429-1690C>T		intron	N/A	NP_001305244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSCB	ENST00000216027.8	TSL:1 MANE Select	c.569-1690C>T		intron	N/A	ENSP00000216027.3
	HSCB	ENST00000913001.1		c.563-1690C>T		intron	N/A	ENSP00000583060.1
	HSCB	ENST00000910455.1		c.541+896C>T		intron	N/A	ENSP00000580514.1

Frequencies

GnomAD3 genomes AF: 0.0702 AC: 10671 AN: 152100 Hom.: 448 Cov.: 31

Gnomad AFR AF: 0.0780

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0577

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0932

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0513

Gnomad OTH AF: 0.0598

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0702 AC: 10692 AN: 152218 Hom.: 454 Cov.: 31 AF XY: 0.0731 AC XY: 5443 AN XY: 74418

African (AFR) AF: 0.0783 AC: 3255 AN: 41556

American (AMR) AF: 0.0583 AC: 890 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3472

East Asian (EAS) AF: 0.174 AC: 901 AN: 5178

South Asian (SAS) AF: 0.135 AC: 651 AN: 4822

European-Finnish (FIN) AF: 0.0932 AC: 987 AN: 10586

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0512 AC: 3485 AN: 68010

Other (OTH) AF: 0.0597 AC: 126 AN: 2112

Alfa AF: 0.0602 Hom.: 283

Bravo AF: 0.0653

Asia WGS AF: 0.142 AC: 493 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.7
DANN	Benign	0.79
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5997391; hg19: chr22-29145539;