16-176693-C-G

Position:

• chr16-176693-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000558.5(HBA1):​c.-24C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 148,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (0 hom., cov: 29)
  • Exomes 𝑓: 0.063 (33 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.68

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-176693-C-G is Benign according to our data. Variant chr16-176693-C-G is described in ClinVar as [Benign]. Clinvar id is 439096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5	c.-24C>G		5_prime_UTR_variant	1/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA1	ENST00000320868.9	c.-24C>G		5_prime_UTR_variant	1/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1			upstream_gene_variant		1
HBA1	ENST00000397797.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7404 AN: 148618 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0964

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0781

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.0723

Gnomad OTH AF: 0.0616

GnomAD3 exomes AF: 0.0519 AC: 12127 AN: 233582 Hom.: 8 AF XY: 0.0556 AC XY: 7047 AN XY: 126816

Gnomad AFR exome AF: 0.00861

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0745

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0651

Gnomad OTH exome AF: 0.0589

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0626 AC: 87247 AN: 1393904 Hom.: 33 Cov.: 32 AF XY: 0.0634 AC XY: 43926 AN XY: 692460

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.0330

Gnomad4 ASJ exome AF: 0.0999

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.0708

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0676

Gnomad4 OTH exome AF: 0.0604

GnomAD4 genome AF: 0.0498 AC: 7401 AN: 148734 Hom.: 0 Cov.: 29 AF XY: 0.0481 AC XY: 3498 AN XY: 72784

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.0546

Gnomad4 ASJ AF: 0.0964

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0779

Gnomad4 FIN AF: 0.0358

Gnomad4 NFE AF: 0.0724

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0772 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 31478238) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

alpha Thalassemia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.92
DANN	Benign	0.45

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: rs374054030; hg19: chr16-226692;