Variant 6-135002837-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006620.4(HBS1L):c.436C>G(p.Pro146Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

HBS1L
NM_006620.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.381

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.038858235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HBS1L	NM_006620.4 linkuse as main transcript	c.436C>G	p.Pro146Ala	missense_variant	5/18	ENST00000367837.10
HBS1L	NM_001145158.2 linkuse as main transcript	c.310C>G	p.Pro104Ala	missense_variant	4/17
HBS1L	XM_047418093.1 linkuse as main transcript	c.436C>G	p.Pro146Ala	missense_variant	5/16
HBS1L	NM_001363686.2 linkuse as main transcript	c.-57C>G		5_prime_UTR_variant	6/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBS1L	ENST00000367837.10 linkuse as main transcript	c.436C>G	p.Pro146Ala	missense_variant	5/18	1	NM_006620.4	P1	Q9Y450-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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

Oct 14, 2023

The c.436C>G (p.P146A) alteration is located in exon 5 (coding exon 5) of the HBS1L gene. This alteration results from a C to G substitution at nucleotide position 436, causing the proline (P) at amino acid position 146 to be replaced by an alanine (A). 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

0.048

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.051

T;T;.;T;T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.74

T;T;T;T;T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.039

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.94

N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.20

T;T;T;T;T;D

Sift4G

Benign

0.47

T;T;T;T;.;.

Polyphen

0.0

B;.;B;.;.;.

Vest4

0.065

MutPred

0.10

Gain of MoRF binding (P = 0.036);.;.;.;.;.;

MVP

0.48

MPC

0.16

ClinPred

0.18

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.094

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over