Genetic Variant HBS1L:p.Ile356Ser (chr6-134993774-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006620.4(HBS1L):c.1067T>G(p.Ile356Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,421,378 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I356N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

HBS1L
NM_006620.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

Publications

0 publications found

Variant links:

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]

HBS1L links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HBS1L	NM_006620.4	MANE Select	c.1067T>G	p.Ile356Ser	missense	Exon 8 of 18	NP_006611.1	Q9Y450-1
HBS1L	NM_001145158.2		c.941T>G	p.Ile314Ser	missense	Exon 7 of 17	NP_001138630.1	Q9Y450-4
HBS1L	NM_001363686.2		c.575T>G	p.Ile192Ser	missense	Exon 9 of 19	NP_001350615.1	B7Z524

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HBS1L	ENST00000367837.10	TSL:1 MANE Select	c.1067T>G	p.Ile356Ser	missense	Exon 8 of 18	ENSP00000356811.5	Q9Y450-1
HBS1L	ENST00000527578.5	TSL:1	c.575T>G	p.Ile192Ser	missense	Exon 5 of 15	ENSP00000436256.1	B7Z524
HBS1L	ENST00000949311.1		c.1067T>G	p.Ile356Ser	missense	Exon 8 of 19	ENSP00000619370.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247444

AF XY:

0.00

show subpopulations

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:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1421378

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707570

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32868

American (AMR)

AF:

0.00

AC:

AN:

43954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25188

East Asian (EAS)

AF:

0.00

AC:

AN:

39288

South Asian (SAS)

AF:

0.00

AC:

AN:

80404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1083294

Other (OTH)

AF:

0.00

AC:

AN:

58564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.1

PhyloP100

9.3

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.83

Gain of disorder (P = 0.0283)

MVP

0.89

MPC

0.83

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.98

Mutation Taster

=7/93

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over