6-134969328-T-C

Variant names:

• chr6-134969328-T-C
• rs1489792079
• NM_006620.4:c.1808A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006620.4(HBS1L):​c.1808A>G​(p.His603Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBS1L NM_006620.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBS1L	NM_006620.4	c.1808A>G	p.His603Arg	missense_variant	Exon 16 of 18	ENST00000367837.10	NP_006611.1
HBS1L	NM_001145158.2	c.1682A>G	p.His561Arg	missense_variant	Exon 15 of 17		NP_001138630.1
HBS1L	NM_001363686.2	c.1316A>G	p.His439Arg	missense_variant	Exon 17 of 19		NP_001350615.1
HBS1L	XM_047418093.1	c.1798-2855A>G		intron_variant	Intron 15 of 15		XP_047274049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBS1L	ENST00000367837.10	c.1808A>G	p.His603Arg	missense_variant	Exon 16 of 18	1	NM_006620.4	ENSP00000356811.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250618 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135454

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 SAS 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: 0.00000137 AC: 2 AN: 1458722 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1808A>G (p.H603R) alteration is located in exon 16 (coding exon 16) of the HBS1L gene. This alteration results from a A to G substitution at nucleotide position 1808, causing the histidine (H) at amino acid position 603 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T;.;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.6	H;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.9	D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.98	D;.;.;D;.
Vest4		0.95
MutPred		0.71		Loss of sheet (P = 0.0181);.;.;.;.;
MVP		0.85
MPC		0.56
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs1489792079; hg19: chr6-135290466;