rs63749948

Variant names:

• chr16-177314-C-A
• rs63749948
• NM_000558.5:c.332C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-177314-C-A
• chr16-177314-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000558.5(HBA1):​c.332C>A​(p.Ala111Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A111T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 5.40
• Publications: 5 publications found

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) 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]

HBA1 Gene-Disease associations (from GenCC):

• HBA1-related alpha thalassemia spectrum

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• alpha thalassemia spectrum

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen
• unstable hemoglobin disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Heinz body anemia

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000294436 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 14 uncertain in NM_000558.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 16-177314-C-A is Pathogenic according to our data. Variant chr16-177314-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 15800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000558.5. 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
	HBA1	NM_000558.5	MANE Select	c.332C>A	p.Ala111Asp	missense	Exon 3 of 3	NP_000549.1	P69905

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA1	ENST00000320868.9	TSL:1 MANE Select	c.332C>A	p.Ala111Asp	missense	Exon 3 of 3	ENSP00000322421.5	P69905
	HBA1	ENST00000472694.1	TSL:1	n.468C>A		non_coding_transcript_exon	Exon 2 of 2
	HBA1	ENST00000397797.1	TSL:2	c.236C>A	p.Ala79Asp	missense	Exon 3 of 3	ENSP00000380899.1	G3V1N2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460794 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726694

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111780

Other (OTH) AF: 0.0000166 AC: 1 AN: 60324

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693798:Methemoglobinemia, alpha type;C4693823:Erythrocytosis, familial, 7 (1)
1	-	-	not provided (1)
-	-	-	HEMOGLOBIN PETAH TIKVA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
PhyloP100		5.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.82
MutPred		0.88		Gain of relative solvent accessibility (P = 0.0479)
MVP		1.0
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.98
gMVP		0.98
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs63749948; hg19: chr16-227313;