chr22-28749423-T-C

Variant names:

• chr22-28749423-T-C
• rs714191
• NM_172002.5:c.569-1818T>C

Variant summary

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

The NM_172002.5(HSCB):​c.569-1818T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 152,050 control chromosomes in the GnomAD database, including 4,557 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 0.24 (4557 hom., cov: 31)
• Consequence: HSCB NM_172002.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 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.569-1818T>C		intron	N/A	NP_741999.3
	HSCB	NM_001318314.2		c.424-1818T>C		intron	N/A	NP_001305243.1
	HSCB	NM_001318315.2		c.429-1818T>C		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.569-1818T>C		intron	N/A	ENSP00000216027.3
	HSCB	ENST00000398941.6	TSL:2	c.429-1818T>C		intron	N/A	ENSP00000381914.2
	HSCB	ENST00000420442.5	TSL:5	n.*142-1818T>C		intron	N/A	ENSP00000416679.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35841 AN: 151930 Hom.: 4550 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.266

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

GnomAD4 genome AF: 0.236 AC: 35882 AN: 152050 Hom.: 4557 Cov.: 31 AF XY: 0.241 AC XY: 17883 AN XY: 74324

African (AFR) AF: 0.260 AC: 10783 AN: 41458

American (AMR) AF: 0.306 AC: 4669 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1234 AN: 3470

East Asian (EAS) AF: 0.433 AC: 2243 AN: 5176

South Asian (SAS) AF: 0.282 AC: 1356 AN: 4814

European-Finnish (FIN) AF: 0.209 AC: 2212 AN: 10584

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.185 AC: 12557 AN: 67994

Other (OTH) AF: 0.265 AC: 560 AN: 2110

Alfa AF: 0.210 Hom.: 2772

Bravo AF: 0.249

Asia WGS AF: 0.368 AC: 1276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.60
PhyloP100		0.078
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: rs714191; hg19: chr22-29145411;