6-135002823-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006620.4(HBS1L):c.450G>C(p.Gln150His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,612,204 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: HBS1L NM_006620.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.43

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039607882).
• BP6: Variant 6-135002823-C-G is Benign according to our data. Variant chr6-135002823-C-G is described in ClinVar as [Benign]. Clinvar id is 720121.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBS1L	NM_006620.4	c.450G>C	p.Gln150His	missense_variant	5/18	ENST00000367837.10
HBS1L	NM_001145158.2	c.324G>C	p.Gln108His	missense_variant	4/17
HBS1L	XM_047418093.1	c.450G>C	p.Gln150His	missense_variant	5/16
HBS1L	NM_001363686.2	c.-43G>C		5_prime_UTR_variant	6/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBS1L	ENST00000367837.10	c.450G>C	p.Gln150His	missense_variant	5/18	1	NM_006620.4	P1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152022 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00812

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000705 AC: 177 AN: 251052 Hom.: 1 AF XY: 0.000568 AC XY: 77 AN XY: 135676

Gnomad AFR exome AF: 0.00930

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000201 AC: 293 AN: 1460064 Hom.: 1 Cov.: 30 AF XY: 0.000167 AC XY: 121 AN XY: 726414

Gnomad4 AFR exome AF: 0.00613

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000746

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152140 Hom.: 4 Cov.: 32 AF XY: 0.00233 AC XY: 173 AN XY: 74380

Gnomad4 AFR AF: 0.00805

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000922 Hom.: 0

Bravo AF: 0.00277

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.099	T;T;.;T;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T;T;T;T;T
MetaRNN	Benign	0.0040	T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.
MutationTaster	Benign	0.76	D;D;D;D;D;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.11	T;D;T;T;T;D
Sift4G	Benign	0.12	T;T;T;T;.;.
Polyphen		0.39	B;.;P;.;.;.
Vest4		0.19
MutPred		0.051		Loss of methylation at K145 (P = 0.0903);.;.;.;.;.;
MVP		0.69
MPC		0.26
ClinPred		0.011	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.26

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

Other links and lift over

dbSNP: rs35697718; hg19: chr6-135323961;