16-173548-T-A

Variant names:

• chr16-173548-T-A
• rs41397847
• NM_000517.6:c.377T>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000517.6(HBA2):​c.377T>A​(p.Leu126Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L126R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 26)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.78
• Publications: 10 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000517.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-173548-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-173548-T-A is Pathogenic according to our data. Variant chr16-173548-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 869221.Status of the report is no_assertion_criteria_provided, 0 stars.

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.377T>A	p.Leu126Gln	missense	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.377T>A	p.Leu126Gln	missense	Exon 3 of 3	ENSP00000251595.6	P69905
	HBA2	ENST00000482565.1	TSL:1	n.513T>A		non_coding_transcript_exon	Exon 2 of 2
	HBA2	ENST00000397806.1	TSL:2	c.281T>A	p.Leu94Gln	missense	Exon 3 of 3	ENSP00000380908.1	G3V1N2

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	alpha Thalassemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.70	D
PhyloP100		2.8
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Vest4		0.82
MutPred		0.94		Gain of disorder (P = 0.0174)
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.91
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs41397847; hg19: chr16-223547;