chr16-176736-A-G

Position:

• chr16-176736-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000558.5(HBA1):​c.20A>G​(p.Asp7Gly) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D7A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:2 O:1
• Conservation: PhyloP100: 5.07

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5	c.20A>G	p.Asp7Gly	missense_variant	1/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.20A>G	p.Asp7Gly	missense_variant	1/3	1	NM_000558.5	ENSP00000322421	P1
HBA1	ENST00000472694.1	n.39A>G		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000397797.1	c.-28A>G		5_prime_UTR_variant	1/3	2		ENSP00000380899
HBA1	ENST00000487791.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1433546 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 711574

Gnomad4 AFR exome AF: 0.00

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.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Erythrocytosis, familial, 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1996

- -

alpha Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 21, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 06, 2020

The Hb Swan River variant (HBA1: c.20A>G; p.Asp7Gly, also known as Asp6Gly when numbered from the mature protein, rs33986902) is reported in the literature in normal individuals, as well as an individual with erythrocytosis (Como 1989, Harano 1996, HbVar database and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartate at codon 7 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Isopropanol precipitation gives conflicting results, with one study suggesting slight instability and another report suggesting normal stability (Como 1989, Harano 1996). Due to limited information, the clinical significance of the Hb Swan River variant is uncertain at this time. References: HbVar link to Hb Swan River: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=9 Como PF et al. Hb Swan River [alpha 6(A4) Asp----Gly] initial identification in an Australian family. Hemoglobin. 1989;13(4):393-6. Harano T et al. HB Swan River [alpha 6(A4)ASP-->Gly] observed in a Japanese man. Hemoglobin. 1996 Feb;20(1):75-8. -

HEMOGLOBIN SWAN RIVER Other:1

other, no assertion criteria provided

literature only

OMIM

Nov 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.094
Eigen_PC	Benign	0.045
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.69
MutPred		0.81		Gain of MoRF binding (P = 0.0081);
MVP		1.0
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.98
gMVP		0.90

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: rs33986902; hg19: chr16-226735;