6-134993823-T-C

Variant names:

• chr6-134993823-T-C
• rs936892072
• NM_006620.4:c.1018A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006620.4(HBS1L):​c.1018A>G​(p.Ile340Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000893 in 1,455,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I340T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: HBS1L NM_006620.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20279992).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006620.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBS1L	NM_006620.4	MANE Select	c.1018A>G	p.Ile340Val	missense	Exon 8 of 18	NP_006611.1	Q9Y450-1
	HBS1L	NM_001145158.2		c.892A>G	p.Ile298Val	missense	Exon 7 of 17	NP_001138630.1	Q9Y450-4
	HBS1L	NM_001363686.2		c.526A>G	p.Ile176Val	missense	Exon 9 of 19	NP_001350615.1	B7Z524

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBS1L	ENST00000367837.10	TSL:1 MANE Select	c.1018A>G	p.Ile340Val	missense	Exon 8 of 18	ENSP00000356811.5	Q9Y450-1
	HBS1L	ENST00000527578.5	TSL:1	c.526A>G	p.Ile176Val	missense	Exon 5 of 15	ENSP00000436256.1	B7Z524
	HBS1L	ENST00000949311.1		c.1018A>G	p.Ile340Val	missense	Exon 8 of 19	ENSP00000619370.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000893 AC: 13 AN: 1455248 Hom.: 0 Cov.: 28 AF XY: 0.00000967 AC XY: 7 AN XY: 723958

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1107654

Other (OTH) AF: 0.00 AC: 0 AN: 60022

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PhyloP100		4.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.084
Sift	Benign	0.74	T
Sift4G	Benign	0.84	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.69		Loss of sheet (P = 0.0817)
MVP		0.33
MPC		0.14
ClinPred		0.79	D
GERP RS		4.9
Varity_R		0.11
gMVP		0.28
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs936892072; hg19: chr6-135314961; COSMIC: COSV107453630; COSMIC: COSV107453630;