16-177103-C-G

Position:

• chr16-177103-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_000558.5(HBA1):​c.270C>G​(p.His90Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,404,836 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).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (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: 0.183

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• BP6: Variant 16-177103-C-G is Benign according to our data. Variant chr16-177103-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15885.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5	c.270C>G	p.His90Gln	missense_variant	2/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.270C>G	p.His90Gln	missense_variant	2/3	1	NM_000558.5	ENSP00000322421.5
HBA1	ENST00000472694.1	n.406C>G		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1	n.239C>G		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1	c.174C>G	p.His58Gln	missense_variant	2/3	2		ENSP00000380899.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1404836 Hom.: 0 Cov.: 27 AF XY: 0.00000287 AC XY: 2 AN XY: 696958

Gnomad4 AFR exome AF: 0.0000617

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 18, 2024

Variant summary: HBA1 c.270C>G (p.His90Gln, also known as Hb Buffalo, alpha89(FG1)His>Gln) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.270C>G has been reported in the literature in healthy individuals (Hoyer_2002). The report does not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12403494, 15166271). ClinVar contains an entry for this variant (Variation ID: 15885). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 27, 2020

- -

HEMOGLOBIN BUFFALO Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.62	T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.41	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.32	T;T
Vest4		0.50
MutPred		0.80		Loss of catalytic residue at L92 (P = 0.0763);.;
MVP		1.0
ClinPred		0.95	D
GERP RS		2.2
Varity_R		0.90
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs1061009; hg19: chr16-227102;