rs63750067

Variant names:

• chr16-173692-A-G
• rs63750067
• NM_000517.6:c.*92A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PS3 PP5_Very_Strong BP4 BS2_Supporting

The NM_000517.6(HBA2):​c.*92A>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 0.0000383 in 1,542,178 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000601205: Functional studies report this variant results nonfunctional and unstable mRNA (PMIDs: 1581238 (1992), 1281602 (1992)).".

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000039 (7 hom.)
• Consequence: HBA2 NM_000517.6 3_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.09
• Publications: 8 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000601205: Functional studies report this variant results nonfunctional and unstable mRNA (PMIDs: 1581238 (1992), 1281602 (1992)).
• PP5: Variant 16-173692-A-G is Pathogenic according to our data. Variant chr16-173692-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.*92A>G		3_prime_UTR	Exon 3 of 3	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.*92A>G		3_prime_UTR	Exon 3 of 3	ENSP00000251595.6	P69905
	HBA2	ENST00000866237.1		c.*92A>G		3_prime_UTR	Exon 3 of 3	ENSP00000536296.1
	HBA2	ENST00000397806.1	TSL:2	c.*92A>G		3_prime_UTR	Exon 3 of 3	ENSP00000380908.1	G3V1N2

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 4 AN: 149158 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000432

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000395 AC: 55 AN: 1393020 Hom.: 7 Cov.: 23 AF XY: 0.0000476 AC XY: 33 AN XY: 693970

African (AFR) AF: 0.00 AC: 0 AN: 28192

American (AMR) AF: 0.0000240 AC: 1 AN: 41654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25296

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38484

South Asian (SAS) AF: 0.000296 AC: 24 AN: 81160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51578

Middle Eastern (MID) AF: 0.00217 AC: 12 AN: 5518

European-Non Finnish (NFE) AF: 0.00000658 AC: 7 AN: 1063656

Other (OTH) AF: 0.000174 AC: 10 AN: 57482

GnomAD4 genome AF: 0.0000268 AC: 4 AN: 149158 Hom.: 0 Cov.: 25 AF XY: 0.0000550 AC XY: 4 AN XY: 72766

African (AFR) AF: 0.00 AC: 0 AN: 38792

American (AMR) AF: 0.00 AC: 0 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000432 AC: 2 AN: 4630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000776 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
1	-	-	alpha Thalassemia (1)
1	-	-	alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 (1)
1	-	-	Alpha-thalassemia-2, nondeletional (1)
1	-	-	beta Thalassemia (1)
1	-	-	Hemoglobin H disease (1)
1	-	-	Hemoglobin H disease, nondeletional (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		1.1
Mutation Taster		=32/68	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs63750067; hg19: chr16-223691;