rs587776826

Positions:

• chr16-173146-CACCAAGA-CTACTTC

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000517.6(HBA2):​c.118_124delinsTACTTC​(p.Thr40TyrfsTer10) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 11)
• Consequence: HBA2 NM_000517.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.80

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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-173147-ACCAAGA-TACTTC is Pathogenic according to our data. Variant chr16-173147-ACCAAGA-TACTTC is described in ClinVar as [Pathogenic]. Clinvar id is 15657.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.118_124delinsTACTTC	p.Thr40TyrfsTer10	frameshift_variant	2/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.118_124delinsTACTTC	p.Thr40TyrfsTer10	frameshift_variant	2/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000484216.1	c.87_93delinsTACTTC	p.Thr30TyrfsTer10	frameshift_variant	2/2	1		ENSP00000495899
HBA2	ENST00000482565.1	n.254_260delinsTACTTC		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.22_28delinsTACTTC	p.Thr8TyrfsTer10	frameshift_variant	2/3	2		ENSP00000380908

Frequencies

GnomAD3 genomes Cov.: 11

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 11

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alpha trait thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1997

- -

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: rs587776826; hg19: chr16-223146;