16-177120-C-T

Variant names:

• chr16-177120-C-T
• rs33931314
• NM_000558.5:c.287C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000558.5(HBA1):​c.287C>T​(p.Pro96Leu) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P96R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 7.15
• Publications: 7 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):

• alpha thalassemia spectrum

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 24 uncertain in NM_000558.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 16-177120-C-T is Pathogenic according to our data. Variant chr16-177120-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15730.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.287C>T	p.Pro96Leu	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.287C>T	p.Pro96Leu	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.07e-7 AC: 1 AN: 1414336 Hom.: 0 Cov.: 28 AF XY: 0.00000142 AC XY: 1 AN XY: 702278

African (AFR) AF: 0.00 AC: 0 AN: 32514

American (AMR) AF: 0.0000247 AC: 1 AN: 40468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25552

East Asian (EAS) AF: 0.00 AC: 0 AN: 38104

South Asian (SAS) AF: 0.00 AC: 0 AN: 83060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089246

Other (OTH) AF: 0.00 AC: 0 AN: 58708

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Pathogenic:1 Uncertain:1

Sep 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBA1 c.287C>T (p.Pro96Leu; aka Hb Georgia) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-07 in 1560800 control chromosomes in the gnomAD database (v4.1 dataset). A variant, described as c.287C>T in the alpha-globin gene (the gene, i.e. HBA1 or HBA2, was not specified), has been reported in the literature in an individual affected with hemolytic anemia, however a co-occurring (potentially pathogenic) HBB variant could explain the phenotype (Medri_2022), moreover, a family member, who carried the variant in isolation didn't show signs of hemolysis. The IthaNet database reports the variant c.287C>T in both the HBA1 and HBA2 genes as Benign / Likely Benign (IthaIDs: 3718,683). To our knowledge, no experimental evidence demonstrating an impact on HBA1 protein function has been reported; however, the c.287C>T variant in HBA2 has been reported to result in increased oxygen affinity (PMID 5012316), but no effect on mRNA synthesis (PMID 8745431). The following publication have been ascertained in the context of this evaluation (PMID: 35397565). ClinVar contains an entry for this variant (Variation ID: 15730). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Jan 13, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HEMOGLOBIN G (GEORGIA) Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.84	D
PhyloP100		7.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-9.5	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.90
MutPred		0.99		Loss of ubiquitination at K91 (P = 0.069);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		0.0049	Neutral
Varity_R		0.97
gMVP		0.98

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: rs33931314; hg19: chr16-227119;