16-177026-G-C

Position:

chr16-177026-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000558.5(HBA1):c.193G>C(p.Asp65His) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D65Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 0.103

Variant links:

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 links:

HBA1 (HGNC:):

HBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5 linkuse as main transcript	c.193G>C	p.Asp65His	missense_variant	2/3	ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBA1	ENST00000320868.9 linkuse as main transcript	c.193G>C	p.Asp65His	missense_variant	2/3	1	NM_000558.5	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1 linkuse as main transcript	n.329G>C		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1 linkuse as main transcript	n.162G>C		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1 linkuse as main transcript	c.97G>C	p.Asp33His	missense_variant	2/3	2		ENSP00000380899.1	G3V1N2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000444

AC:

AN:

135032

Hom.:

AF XY:

0.0000545

AC XY:

AN XY:

73338

show subpopulations

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 SAS exome

AF:

0.000264

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000191

AC:

AN:

1255726

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

626094

show subpopulations

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:

0.000307

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000302

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 28, 2024	The HBA1 c.193G>C (p.Asp65His) variant has been reported as having normal stability (HbVar (http://globin.cse.psu.edu/) and PMID: 31553106 (2020)). Additionally, in the published literature, individuals who are heterozygous for this variant are reported to be asymptomatic and have a normal clinical presentation (PMID: 7803274 (1994), 32597250 (2020), 32769347 (2020)). However, the variant may have clinical significance where beta-thalassemia trait occurs or during pregnancy (HbVar (http://globin.cse.psu.edu/), PMID: 4646552 (1972), 25354131 (2014), 28526955 (2017)). A possible association with lower MCH and MCV values has been reported in one study (PMID: 33887194 (2021)). The frequency of this variant in the general population, 0.00026 (6/22758 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 11, 2022	The Hb Q-India variant (HBA1: c.193G>C; p.Asp65His, also known as Asp64His when numbered from the mature protein, rs33984024) is reported in the literature in several families with beta-thalassemia major and minor, but did not alter the beta-thalassemia phenotype (see link to HbVar and references therein, Bhat 2010). It has been described as a stable hemoglobin variant (Molchanova 1994) and did not alter the phenotype in patients with HbS (Parab 2015). One study suggests that some individuals heterozygous for Hb Q-India exhibit microcytosis and anemia (Panigrahi 2005), though the clinical presentations are highly variable even within a family. This variant is reported in ClinVar (Variation ID: 15803). This variant is found in the South Asian population with an allele frequency of 0.004% (6/135032 alleles) in the Genome Aggregation Database. The aspartic acid at codon 65 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.663). However, due to the variable clinical phenotypes associated with Hb Q-India, its clinical significance cannot be determined with certainty. References: Link to HbVar database for Hb Q-India: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=97 Bhat V et al. Characterization of a hemoglobin variant: HbQ-India / IVS 1-1 [G>T]-ß-thalassemia. Indian J Clin Biochem. 2010 25(1):99-104. PMID: 23105893. Molchanova T et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 88(2):300-6. PMID: 7803274. Panigrahi I et al. Hb Q India: is it always benign? Am J Hematol. 2005 78(3):245-6. PMID: 15726591. Parab S et al. Diagnosis of a novel hemoglobinopathy of compound heterozygosity of hemoglobin S/hemoglobin Q India. Clin Chim Acta. 2015 442:33-5. PMID: 25576799. -

alpha Thalassemia

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

HEMOGLOBIN Q (INDIA)

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

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.86

D;T

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.18

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.12

T;T

Vest4

0.67

MutPred

0.90

Gain of MoRF binding (P = 0.0604);.;

MVP

1.0

ClinPred

0.23

GERP RS

2.3

Varity_R

0.54

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over