16-177120-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM1 PM2 PM5 PP3_Strong BP6

The NM_000558.5(HBA1):​c.287C>G​(p.Pro96Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000707 in 1,414,336 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P96L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B: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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-177120-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15730.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• BP6: Variant 16-177120-C-G is Benign according to our data. Variant chr16-177120-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15817.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.287C>G	p.Pro96Arg	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>G	p.Pro96Arg	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414336 Hom.: 0 Cov.: 28 AF XY: 0.00000142 AC XY: 1 AN XY: 702278

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 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: 9.18e-7 AC: 1 AN: 1089246

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb St. Luke's variant (HBA1: c.287C>G; p.Pro96Arg, also known as Pro95Arg when numbered from the mature protein, rs33931314, ClinVar Variation ID: 15817, HbVar ID:160) is reported in the heterozygous state in individuals with normal hematological parameters (see HbVar database and references therein, van Zwieten 2014). Additionally, this variant was found heterozygous in an individual that also carried HbS with normal hematological parameters (Silva 2013). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.908), and functional studies demonstrate increased oxygen affinity (Lorkin 1974). Based on available information, this variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Lorkin PA et al. The oxygen affinity of haemoglobin St. Luke's. FEBS Lett. 1974 Feb 1;39(1):111-4. PMID: 4854984. Silva MR et al. Alpha chain hemoglobins with electrophoretic mobility similar to that of hemoglobin S in a newborn screening program. Rev Bras Hematol Hemoter. 2013;35(2):109-14. PMID: 23741188. van Zwieten R et al. Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones. Hemoglobin. 2014;38(1):1-7. PMID: 24200101.

Mar 05, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HEMOGLOBIN ST. LUKE'S 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	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	0.0	.;.
PhyloP100		7.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.94
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		-0.0014	Neutral
Varity_R		0.95
gMVP		0.98
Mutation Taster		=10/90	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: rs33931314; hg19: chr16-227119;