chr16-173736-A-G

Position:

• chr16-173736-A-G

Variant summary

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

The 16-173736-A-G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 147,998 control chromosomes in the GnomAD database, including 55,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (55503 hom., cov: 30)
  • Exomes 𝑓: 0.83 (354028 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 downstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0180

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-173736-A-G is Benign according to our data. Variant chr16-173736-A-G is described in ClinVar as [Benign]. Clinvar id is 402921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6			downstream_gene_variant		ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11			downstream_gene_variant		1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000397806.1			downstream_gene_variant		2		ENSP00000380908

Frequencies

GnomAD3 genomes AF: 0.859 AC: 127091 AN: 147876 Hom.: 55432 Cov.: 30

Gnomad AFR AF: 0.958

Gnomad AMI AF: 0.790

Gnomad AMR AF: 0.851

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.817

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.835

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.827 AC: 848610 AN: 1025792 Hom.: 354028 Cov.: 14 AF XY: 0.831 AC XY: 433607 AN XY: 521708

Gnomad4 AFR exome AF: 0.962

Gnomad4 AMR exome AF: 0.902

Gnomad4 ASJ exome AF: 0.787

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.955

Gnomad4 FIN exome AF: 0.821

Gnomad4 NFE exome AF: 0.801

Gnomad4 OTH exome AF: 0.837

GnomAD4 genome AF: 0.860 AC: 127223 AN: 147998 Hom.: 55503 Cov.: 30 AF XY: 0.862 AC XY: 62286 AN XY: 72232

Gnomad4 AFR AF: 0.958

Gnomad4 AMR AF: 0.851

Gnomad4 ASJ AF: 0.792

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.961

Gnomad4 FIN AF: 0.831

Gnomad4 NFE AF: 0.799

Gnomad4 OTH AF: 0.836

Alfa AF: 0.842 Hom.: 6658

Bravo AF: 0.867

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 1966/2178= 90.26% -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 05, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 15365991) -

alpha Thalassemia Benign:1

Benign, no assertion criteria provided

curation

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Nov 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.40

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2685121; hg19: chr16-223735;