rs33914470

Variant names:

• chr16-177106-G-C
• rs33914470
• NM_000558.5:c.273G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-177106-G-C
• chr16-177106-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PP3_Strong BP6_Moderate

The NM_000558.5(HBA1):​c.273G>C​(p.Lys91Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 1,404,816 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 benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K91M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:3
• Conservation: PhyloP100: 0.162
• Publications: 3 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 27 uncertain in NM_000558.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• BP6: Variant 16-177106-G-C is Benign according to our data. Variant chr16-177106-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 15707.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.273G>C	p.Lys91Asn	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.273G>C	p.Lys91Asn	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 156290 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000278 AC: 39 AN: 1404816 Hom.: 0 Cov.: 27 AF XY: 0.0000287 AC XY: 20 AN XY: 696994

African (AFR) AF: 0.00 AC: 0 AN: 32420

American (AMR) AF: 0.00 AC: 0 AN: 39432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25412

East Asian (EAS) AF: 0.00 AC: 0 AN: 37834

South Asian (SAS) AF: 0.00 AC: 0 AN: 82184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4156

European-Non Finnish (NFE) AF: 0.0000341 AC: 37 AN: 1085396

Other (OTH) AF: 0.0000342 AC: 2 AN: 58444

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000859 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb J-Broussais variant (HBA1: c.273G>C; p.Lys91Asn, also known as Lys90Asn when numbered from the mature protein; rs33914470, HbVar ID: 142) is reported in the literature in multiple individuals without clinical symptoms and with normal hematology (Molchanova 1994, Turpeinen 1995, HbVar and references therein). This variant is reported in ClinVar (Variation ID: 15707), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The lysine at codon 91 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.559). However, functional studies demonstrate normal stability and oxygen affinity (Molchanova 1994, Turpeinen 1995, HbVar and references therein). Based on available information, this variant is considered to be likely benign. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Molchanova TP et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 Oct;88(2):300-6. PMID: 7803274 Turpeinen U et al. Two alpha-chain hemoglobin variants, Hb Broussais and Hb Cemenelum, characterized by cation-exchange HPLC, isoelectric focusing, and peptide sequencing. Clin Chem. 1995 Apr;41(4):532-6. PMID: 7720241 -

HEMOGLOBIN J (BROUSSAIS) Other:1

Oct 01, 1978

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN BROUSSAIS Other:1

Oct 01, 1978

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN TAGAWA I Other:1

Oct 01, 1978

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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.35	D
PhyloP100		0.16
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.31	T;T
Vest4		0.65
MutPred		0.97		Loss of ubiquitination at K91 (P = 0.0167);.;
MVP		0.99
ClinPred		0.96	D
GERP RS		0.80
PromoterAI		0.034	Neutral
Varity_R		0.84
gMVP		0.97
Mutation Taster		=9/91	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: rs33914470; hg19: chr16-227105;