16-173707-A-G

Position:

• chr16-173707-A-G

Variant summary

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

The NM_000517.6(HBA2):​c.*107A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 148,818 control chromosomes in the GnomAD database, including 73,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (73606 hom., cov: 32)
  • Exomes 𝑓: 0.99 (634691 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.12

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-173707-A-G is Benign according to our data. Variant chr16-173707-A-G is described in ClinVar as [Benign]. Clinvar id is 439108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.*107A>G		3_prime_UTR_variant	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.*107A>G		3_prime_UTR_variant	3/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000397806.1	c.*107A>G		3_prime_UTR_variant	3/3	2		ENSP00000380908
	ENST00000702607.1			upstream_gene_variant
HBA2	ENST00000482565.1			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.994 AC: 147874 AN: 148696 Hom.: 73542 Cov.: 32

Gnomad AFR AF: 0.998

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.992

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.992

Gnomad OTH AF: 0.995

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.992 AC: 1279110 AN: 1288992 Hom.: 634691 Cov.: 20 AF XY: 0.993 AC XY: 639893 AN XY: 644634

Gnomad4 AFR exome AF: 0.999

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.992

Gnomad4 NFE exome AF: 0.991

Gnomad4 OTH exome AF: 0.994

GnomAD4 genome AF: 0.994 AC: 147999 AN: 148818 Hom.: 73606 Cov.: 32 AF XY: 0.995 AC XY: 72346 AN XY: 72698

Gnomad4 AFR AF: 0.998

Gnomad4 AMR AF: 0.993

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 0.992

Gnomad4 NFE AF: 0.992

Gnomad4 OTH AF: 0.995

Alfa AF: 0.994 Hom.: 9510

Bravo AF: 0.994

Asia WGS AF: 0.999 AC: 3191 AN: 3194

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

alpha Thalassemia Benign:3

Benign, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 25, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 26, 2024	Variant summary: HBA2 c.*107A>G is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.99 in 1,431,278 control chromosomes (gnomAD v4), suggesting that it is the major allele and therefore benign. ClinVar contains an entry for this variant (Variation ID: 439108). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Erythrocytosis, familial, 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.92
DANN	Benign	0.43

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: rs2541640; hg19: chr16-223706;