dbSNP rs1774318038: HBS1L:p.Ala641Ser (chr6-134966451-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006620.4(HBS1L):c.1921G>T(p.Ala641Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,416 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: 6.9e-7 ( 0 hom. )

Consequence

HBS1L
NM_006620.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.35

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBS1L	NM_006620.4 link	c.1921G>T	p.Ala641Ser	missense_variant	Exon 17 of 18	ENST00000367837.10	NP_006611.1	Q9Y450-1D9YZV0
HBS1L	NM_001145158.2 link	c.1795G>T	p.Ala599Ser	missense_variant	Exon 16 of 17		NP_001138630.1	Q9Y450-4
HBS1L	NM_001363686.2 link	c.1429G>T	p.Ala477Ser	missense_variant	Exon 18 of 19		NP_001350615.1
HBS1L	XM_047418093.1 link	c.*11G>T		3_prime_UTR_variant	Exon 16 of 16		XP_047274049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBS1L	ENST00000367837.10 link	c.1921G>T	p.Ala641Ser	missense_variant	Exon 17 of 18	1	NM_006620.4	ENSP00000356811.5		Q9Y450-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444416

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717826

show subpopulations

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:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;T;.;T

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Pathogenic

3.1

M;.;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.4

N;N;N;N;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D;D

Polyphen

1.0

D;.;.;D;.

Vest4

0.81

MutPred

0.68

Loss of sheet (P = 0.0181);.;.;.;.;

MVP

0.59

MPC

0.65

ClinPred

0.99

GERP RS

6.0

Varity_R

0.84

gMVP

0.78

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over