rs281860626

Positions:

• chr16-173143-C-CGAA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM4_Supporting PP5_Moderate

The NM_000517.6(HBA2):​c.114_115insGAA​(p.Pro38_Thr39insGlu) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 10)
• Consequence: HBA2 NM_000517.6 inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.517

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000517.6
• PM4: Nonframeshift variant in NON repetitive region in NM_000517.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-173143-C-CGAA is Pathogenic according to our data. Variant chr16-173143-C-CGAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 619846.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.114_115insGAA	p.Pro38_Thr39insGlu	inframe_insertion	2/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.114_115insGAA	p.Pro38_Thr39insGlu	inframe_insertion	2/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1	c.83_84insGAA	p.Pro28_Thr29insGlu	inframe_insertion	2/2	1
HBA2	ENST00000482565.1	n.250_251insGAA		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.18_19insGAA	p.Pro6_Thr7insGlu	inframe_insertion	2/3	2

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 9

GnomAD4 genome Cov.: 10

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 30, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs281860626; hg19: chr16-223142;