6-135002758-T-C

Position:

chr6-135002758-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006620.4(HBS1L):c.515A>G(p.Gln172Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,612,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HBS1L
NM_006620.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20639393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HBS1L	NM_006620.4 linkuse as main transcript	c.515A>G	p.Gln172Arg	missense_variant	5/18	ENST00000367837.10	NP_006611.1
HBS1L	NM_001145158.2 linkuse as main transcript	c.389A>G	p.Gln130Arg	missense_variant	4/17		NP_001138630.1
HBS1L	NM_001363686.2 linkuse as main transcript	c.23A>G	p.Gln8Arg	missense_variant	6/19		NP_001350615.1
HBS1L	XM_047418093.1 linkuse as main transcript	c.515A>G	p.Gln172Arg	missense_variant	5/16		XP_047274049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBS1L	ENST00000367837.10 linkuse as main transcript	c.515A>G	p.Gln172Arg	missense_variant	5/18	1	NM_006620.4	ENSP00000356811	P1	Q9Y450-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251256

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726552

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.515A>G (p.Q172R) alteration is located in exon 5 (coding exon 5) of the HBS1L gene. This alteration results from a A to G substitution at nucleotide position 515, causing the glutamine (Q) at amino acid position 172 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

Benign

0.27

BayesDel_addAF

Benign

-0.0078

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;T;.;T;.;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D

M_CAP

Benign

0.058

MetaRNN

Benign

0.21

T;T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.1

M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.49

T;D;T;T;T;D;D

Sift4G

Benign

0.53

T;T;T;T;T;T;.

Polyphen

0.97

D;.;.;D;.;.;.

Vest4

0.52

MutPred

0.10

Gain of MoRF binding (P = 0.0378);.;.;.;.;.;.;

MVP

0.80

MPC

0.64

ClinPred

0.35

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over