rs33991779

Positions:

• chr16-177111-G-A
• chr16-177111-G-C
• chr16-177111-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000558.5(HBA1):​c.278G>A​(p.Arg93Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Pathogenic; other no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.16

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 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 chr16-177111-G-T is described in ClinVar as [Pathogenic, other]. Clinvar id is 15711.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 16-177111-G-A is Pathogenic according to our data. Variant chr16-177111-G-A is described in ClinVar as [Pathogenic, other]. Clinvar id is 15752.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5	c.278G>A	p.Arg93Gln	missense_variant	2/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA1	ENST00000320868.9	c.278G>A	p.Arg93Gln	missense_variant	2/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1	n.414G>A		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1	n.247G>A		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1	c.182G>A	p.Arg61Gln	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Erythrocytosis, familial, 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1986

- -

HEMOGLOBIN J (CAPE TOWN) 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	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	0.071
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.83	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0090	D;D
Vest4		0.65
MutPred		0.91		Loss of ubiquitination at K91 (P = 0.0578);.;
MVP		1.0
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.98
gMVP		0.91

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: rs33991779; hg19: chr16-227110;