6-135002834-C-T

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.439G>A(p.Val147Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00854 in 1,610,010 control chromosomes in the GnomAD database, including 90 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0089 (86 hom.)
• Consequence: HBS1L NM_006620.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.925

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=0.0033268034).
• BP6: Variant 6-135002834-C-T is Benign according to our data. Variant chr6-135002834-C-T is described in ClinVar as [Benign]. Clinvar id is 777171.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.439G>A	p.Val147Ile	missense_variant	5/18	ENST00000367837.10
HBS1L	NM_001145158.2	c.313G>A	p.Val105Ile	missense_variant	4/17
HBS1L	XM_047418093.1	c.439G>A	p.Val147Ile	missense_variant	5/16
HBS1L	NM_001363686.2	c.-54G>A		5_prime_UTR_variant	6/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBS1L	ENST00000367837.10	c.439G>A	p.Val147Ile	missense_variant	5/18	1	NM_006620.4	P1

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152120 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00539 AC: 1352 AN: 250820 Hom.: 10 AF XY: 0.00541 AC XY: 734 AN XY: 135562

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00886 AC: 12922 AN: 1457772 Hom.: 86 Cov.: 29 AF XY: 0.00857 AC XY: 6215 AN XY: 725428

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000604

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00538

GnomAD4 genome AF: 0.00547 AC: 832 AN: 152238 Hom.: 4 Cov.: 31 AF XY: 0.00501 AC XY: 373 AN XY: 74422

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00898 Hom.: 3

Bravo AF: 0.00523

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00837 AC: 72

ExAC AF: 0.00560 AC: 680

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00816

EpiControl AF: 0.00979

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

Jun 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.54
Dann	Benign	0.84
DEOGEN2	Benign	0.056	T;T;.;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.68	T;T;T;T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.0033	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.32	N;N;N;N;N;N
REVEL	Benign	0.090
Sift	Benign	0.29	T;T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;.;.
Polyphen		0.0	B;.;B;.;.;.
Vest4		0.052
MVP		0.30
MPC		0.13
ClinPred		0.00078	T
GERP RS		-7.0
Varity_R		0.022
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111758776; hg19: chr6-135323972;