chr16-173736-A-G

Variant names:

• chr16-173736-A-G
• rs2685121
• NM_000517.6:c.*136A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000517.6(HBA2):​c.*136A>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:6
• Conservation: PhyloP100: -0.0180
• Publications: 12 publications found

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]

HBA2 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Heinz body anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• unstable hemoglobin disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. 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
	HBA2	NM_000517.6	MANE Select	c.*136A>G		downstream_gene	N/A	NP_000508.1	D1MGQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.*136A>G		downstream_gene	N/A	ENSP00000251595.6	P69905
	HBA2	ENST00000482565.1	TSL:1	n.*61A>G		downstream_gene	N/A
	HBA2	ENST00000866237.1		c.*136A>G		downstream_gene	N/A	ENSP00000536296.1

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

African (AFR) AF: 0.962 AC: 20257 AN: 21064

American (AMR) AF: 0.902 AC: 32064 AN: 35566

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 17886 AN: 22720

East Asian (EAS) AF: 1.00 AC: 34159 AN: 34168

South Asian (SAS) AF: 0.955 AC: 67214 AN: 70386

European-Finnish (FIN) AF: 0.821 AC: 39292 AN: 47838

Middle Eastern (MID) AF: 0.776 AC: 3757 AN: 4844

European-Non Finnish (NFE) AF: 0.801 AC: 596112 AN: 743946

Other (OTH) AF: 0.837 AC: 37869 AN: 45260

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

African (AFR) AF: 0.958 AC: 36410 AN: 38008

American (AMR) AF: 0.851 AC: 12846 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2738 AN: 3458

East Asian (EAS) AF: 1.00 AC: 5150 AN: 5152

South Asian (SAS) AF: 0.961 AC: 4386 AN: 4566

European-Finnish (FIN) AF: 0.831 AC: 8793 AN: 10578

Middle Eastern (MID) AF: 0.814 AC: 236 AN: 290

European-Non Finnish (NFE) AF: 0.799 AC: 54219 AN: 67880

Other (OTH) AF: 0.836 AC: 1726 AN: 2064

Alfa AF: 0.894 Hom.: 12831

Bravo AF: 0.867

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	alpha Thalassemia (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.7
DANN	Benign	0.40
PhyloP100		-0.018
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2685121; hg19: chr16-223735;