rs1205587876

Variant names:

• chr6-134978740-G-A
• rs1205587876
• NM_006620.4:c.1736C>T

Variant summary

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

The NM_006620.4(HBS1L):​c.1736C>T​(p.Thr579Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HBS1L NM_006620.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.14
• Publications: 0 publications found

Genes affected

HBS1L (HGNC:4834): (HBS1 like translational GTPase) This gene encodes a member of the GTP-binding elongation factor family. It is expressed in multiple tissues with the highest expression in heart and skeletal muscle. The intergenic region of this gene and the MYB gene has been identified to be a quantitative trait locus (QTL) controlling fetal hemoglobin level, and this region influnces erythrocyte, platelet, and monocyte counts as well as erythrocyte volume and hemoglobin content. DNA polymorphisms at this region associate with fetal hemoglobin levels and pain crises in sickle cell disease. A single nucleotide polymorphism in exon 1 of this gene is significantly associated with severity in beta-thalassemia/Hemoglobin E. Multiple alternatively spliced transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006620.4. 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
	HBS1L	NM_006620.4	MANE Select	c.1736C>T	p.Thr579Ile	missense	Exon 15 of 18	NP_006611.1	Q9Y450-1
	HBS1L	NM_001145158.2		c.1610C>T	p.Thr537Ile	missense	Exon 14 of 17	NP_001138630.1	Q9Y450-4
	HBS1L	NM_001363686.2		c.1244C>T	p.Thr415Ile	missense	Exon 16 of 19	NP_001350615.1	B7Z524

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBS1L	ENST00000367837.10	TSL:1 MANE Select	c.1736C>T	p.Thr579Ile	missense	Exon 15 of 18	ENSP00000356811.5	Q9Y450-1
	HBS1L	ENST00000527578.5	TSL:1	c.1244C>T	p.Thr415Ile	missense	Exon 12 of 15	ENSP00000436256.1	B7Z524
	HBS1L	ENST00000527005.5	TSL:1	n.1255C>T		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249736 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457930 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725338

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 85650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109916

Other (OTH) AF: 0.00 AC: 0 AN: 60196

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.78
MutPred		0.46		Loss of methylation at R580 (P = 0.0525)
MVP		0.65
MPC		0.70
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.59
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1205587876; hg19: chr6-135299878;