rs63750751

Variant names:

• chr16-177340-C-T
• rs63750751
• NM_000558.5:c.358C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PP3_Strong PP5_Very_Strong

The NM_000558.5(HBA1):​c.358C>T​(p.Pro120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,180 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002556071: In vitro binding assays indicate that while the variant protein is capable of forming dimers, it does not interact with alpha hemoglobin stabilizing proteins or beta subunits, leading to destabilization and increased proteolytic degredation (Yu_2009)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.35
• Publications: 11 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002556071: In vitro binding assays indicate that while the variant protein is capable of forming dimers, it does not interact with alpha hemoglobin stabilizing proteins or beta subunits, leading to destabilization and increased proteolytic degredation (Yu_2009).; SCV001160280: Functional studies of the variant protein demonstrate impaired binding to alpha hemoglobin stabilizing protein and beta globin, leading to destabilization and increased proteolytic degradation (Yu 2009). PMID: 19349619; SCV001469516: Experimental studies indicate this variant disrupts binding of the alpha globin chains to the AHSP (alpha hemoglobin stabilizing protein) and results in an unstable hemoglobin complex (PMIDs: 21950764 (2011), 19349619 (2009), 17052927(2006)).; SCV002601224: Published functional studies demonstrate a damaging effect on the interaction with alpha hemoglobin stabilizing protein and the beta subunit (Yu X et al., 2009; Wajcman H et al., 2011)
• PM1: In a helix (size 18) in uniprot entity HBA_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000558.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 16-177340-C-T is Pathogenic according to our data. Variant chr16-177340-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 811900.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.358C>T	p.Pro120Ser	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.358C>T	p.Pro120Ser	missense	Exon 3 of 3	ENSP00000322421.5	P69905
	HBA1	ENST00000472694.1	TSL:1	n.494C>T		non_coding_transcript_exon	Exon 2 of 2
	HBA1	ENST00000397797.1	TSL:2	c.262C>T	p.Pro88Ser	missense	Exon 3 of 3	ENSP00000380899.1	G3V1N2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.0000566 AC: 14 AN: 247332 AF XY: 0.0000447

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000628

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460978 Hom.: 1 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 726802

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.000157 AC: 7 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111742

Other (OTH) AF: 0.000133 AC: 8 AN: 60346

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152202 Hom.: 1 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	alpha Thalassemia (3)
3	-	-	not provided (3)
1	-	-	alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693798:Methemoglobinemia, alpha type;C4693823:Erythrocytosis, familial, 7 (1)
1	-	-	Erythrocytosis, familial, 7 (1)
1	-	-	HBA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.39	D
PhyloP100		3.3
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Vest4		0.69
MutPred		0.88		Loss of phosphorylation at T119 (P = 0.1015)
MVP		1.0
ClinPred		0.53	D
GERP RS		0.94
Varity_R		0.90
gMVP		0.94
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs63750751; hg19: chr16-227339;