rs111033603

Variant names:

• chr16-172914-T-C
• rs111033603
• NM_000517.6:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-172914-T-C
• chr16-172914-T-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_000517.6(HBA2):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: HBA2 NM_000517.6 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.03
• Publications: 3 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, 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

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 25 pathogenic variants. Next in-frame start position is after 33 codons. Genomic position: 173126. Lost 0.226 part of the original CDS.
• PS1: Another start lost variant in NM_000517.6 (HBA2) was described as [Pathogenic] in ClinVar
• PP5: Variant 16-172914-T-C is Pathogenic according to our data. Variant chr16-172914-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 15643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	NP_000508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	ENSP00000251595.6
	HBA2	ENST00000482565.1	TSL:1	n.21T>C		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000294455	ENST00000723699.1		n.209A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000148 AC: 4 AN: 271088 Hom.: 0 Cov.: 0 AF XY: 0.0000138 AC XY: 2 AN XY: 144488

African (AFR) AF: 0.00 AC: 0 AN: 6684

American (AMR) AF: 0.00 AC: 0 AN: 13214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7496

East Asian (EAS) AF: 0.00 AC: 0 AN: 14902

South Asian (SAS) AF: 0.00 AC: 0 AN: 42088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1032

European-Non Finnish (NFE) AF: 0.0000255 AC: 4 AN: 157012

Other (OTH) AF: 0.00 AC: 0 AN: 14378

GnomAD4 genome Cov.: 0

Alfa AF: 0.00196 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	alpha Thalassemia (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	23
DANN	Uncertain	0.98
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.75	D
PhyloP100		2.0
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.86
MutPred		1.0		Loss of stability (P = 0.0171)
MVP		1.0
ClinPred		0.99	D
GERP RS		2.6
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.68
Mutation Taster		=5/195	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: rs111033603; hg19: chr16-222913;