6-134966324-A-C

Position:

• chr6-134966324-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006620.4(HBS1L):​c.2043+5T>G variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,604,808 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (16 hom.)
• Consequence: HBS1L NM_006620.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.003293
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.302

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-134966324-A-C is Benign according to our data. Variant chr6-134966324-A-C is described in ClinVar as [Benign]. Clinvar id is 778253.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0055 (837/152286) while in subpopulation AFR AF= 0.0169 (704/41568). AF 95% confidence interval is 0.0159. There are 8 homozygotes in gnomad4. There are 390 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBS1L	NM_006620.4	c.2043+5T>G		splice_donor_5th_base_variant, intron_variant		ENST00000367837.10	NP_006611.1
HBS1L	NM_001145158.2	c.1917+5T>G		splice_donor_5th_base_variant, intron_variant			NP_001138630.1
HBS1L	NM_001363686.2	c.1551+5T>G		splice_donor_5th_base_variant, intron_variant			NP_001350615.1
HBS1L	XM_047418093.1			downstream_gene_variant			XP_047274049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBS1L	ENST00000367837.10	c.2043+5T>G		splice_donor_5th_base_variant, intron_variant		1	NM_006620.4	ENSP00000356811	P1

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 837 AN: 152168 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00219 AC: 533 AN: 243084 Hom.: 4 AF XY: 0.00183 AC XY: 240 AN XY: 131258

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000140

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000513

Gnomad OTH exome AF: 0.00237

GnomAD4 exome AF: 0.00102 AC: 1482 AN: 1452522 Hom.: 16 Cov.: 30 AF XY: 0.000961 AC XY: 694 AN XY: 722260

Gnomad4 AFR exome AF: 0.0190

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000167

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000294

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00550 AC: 837 AN: 152286 Hom.: 8 Cov.: 32 AF XY: 0.00524 AC XY: 390 AN XY: 74468

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00218 Hom.: 3

Bravo AF: 0.00644

Asia WGS AF: 0.00173 AC: 6 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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0033
dbscSNV1_RF	Benign	0.070
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: rs113516481; hg19: chr6-135287462;