6-134982499-C-G

Variant names:

• chr6-134982499-C-G
• NM_006620.4:c.1556G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006620.4(HBS1L):​c.1556G>C​(p.Arg519Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: Not reported in ClinVar
• Conservation: PhyloP100: 3.87

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBS1L	NM_006620.4	c.1556G>C	p.Arg519Pro	missense_variant	Exon 13 of 18	ENST00000367837.10	NP_006611.1
HBS1L	NM_001145158.2	c.1430G>C	p.Arg477Pro	missense_variant	Exon 12 of 17		NP_001138630.1
HBS1L	NM_001363686.2	c.1064G>C	p.Arg355Pro	missense_variant	Exon 14 of 19		NP_001350615.1
HBS1L	XM_047418093.1	c.1556G>C	p.Arg519Pro	missense_variant	Exon 13 of 16		XP_047274049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBS1L	ENST00000367837.10	c.1556G>C	p.Arg519Pro	missense_variant	Exon 13 of 18	1	NM_006620.4	ENSP00000356811.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459150 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725954

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;T;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.97	L;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;.;.;D;.
Vest4		0.80
MutPred		0.53		Loss of sheet (P = 0.0817);.;.;.;.;
MVP		0.78
MPC		0.82
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.85
gMVP		0.89

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-135303637;