Genetic Variant HBA1:p.His88Tyr (chr16-177095-C-T) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000558.5(HBA1):c.262C>T(p.His88Tyr) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H88N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:4

Conservation

PhyloP100: 5.42

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:

ENSG00000290010 (HGNC:):

ENSG00000290010 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 16-177095-C-T is Pathogenic according to our data. Variant chr16-177095-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5 link	c.262C>T	p.His88Tyr	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9 link	c.262C>T	p.His88Tyr	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5		P69905

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1402412

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695534

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methemoglobinemia, alpha type

Pathogenic:1

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with HBA1 related disorder (PMID: 10477710). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10477710, 3957697, 6998928). Different missense changes at the same codon (p.His88Asp, p.His88Gln, p.His88Pro) have been reported to be associated with HBA1 related disorder (ClinVar ID: VCV001809522 / PMID: 18310146, 27225845). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1

Dec 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb M-Iwate variant (HBA1: c.262C>T; p.His88Tyr, also known as Hb M-Kankakee, Hb M-Oldenburg, Hb M-Sendai and His87Tyr when numbered from the mature protein, rs28928876, HbVar ID: 134) is reported heterozygous in the literature in multiple individuals affected with chronic cyanosis (See HbVar and references therein, Ameri 1999, Horst 1987). This variant is an autosomal dominant methemoglobinemia variant with significantly reduced oxygen affinity (HbVar, Hayashi 1966). This variant is also reported in ClinVar (Variation ID: 15779) and absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.924). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Ameri A et al. Identification of the molecular genetic defect of patients with methemoglobin M-Kankakee (M-Iwate), alpha87 (F8) His --> Tyr: evidence for an electrostatic model of alphaM hemoglobin assembly. Blood. 1999 Sep 1;94(5):1825-6. PMID: 10477710. Hayashi N et al. Studies on relationships between structure and function of hemoglobin M-Iwate. J Biol Chem. 1966 Jan 10;241(1):79-84. PMID: 5901058. Horst J et al. Hemoglobin M Iwate is caused by a C----T transition in codon 87 of the human alpha 1-globin gene. Hum Genet. 1987 Jan;75(1):53-5. PMID: 3026948. -

HEMOGLOBIN M (KANKAKEE)

Other:1

Sep 01, 1999

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN M (IWATE)

Other:1

Sep 01, 1999

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN M (OLDENBURG)

Other:1

Sep 01, 1999

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN M (SENDAI)

Other:1

Sep 01, 1999

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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.93

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.86

MutPred

0.99

Loss of disorder (P = 0.0404);.;

MVP

1.0

ClinPred

1.0

GERP RS

3.3

Varity_R

0.97

gMVP

0.99

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