16-176759-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000558.5(HBA1):c.43T>C(p.Trp15Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 150,584 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000082 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA1
NM_000558.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.86

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 16-176759-T-C is Pathogenic according to our data. Variant chr16-176759-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439103.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.43T>C	p.Trp15Arg	missense_variant	Exon 1 of 3	ENST00000320868.9	NP_000549.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBA1	ENST00000320868.9 link	c.43T>C	p.Trp15Arg	missense_variant	Exon 1 of 3	1	NM_000558.5	ENSP00000322421.5	P69905
HBA1	ENST00000472694.1 link	n.62T>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA1	ENST00000487791.1 link	n.12T>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA1	ENST00000397797 link	c.-5T>C		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000380899.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150500

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000626

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000168

AC:

AN:

166364

Hom.:

AF XY:

0.000202

AC XY:

AN XY:

89180

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:

0.00114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000218

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000821

AC:

118

AN:

1436916

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

713424

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000259

Gnomad4 SAS exome

AF:

0.00134

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.09e-7

Gnomad4 OTH exome

AF:

0.0000674

GnomAD4 genome

AF:

0.0000199

AC:

AN:

150584

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000627

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000136

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

May 08, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26659599, 26824843, 27830006, 6725558, 15008259, 22924376, 31553106, 26594346, 31304855, 19205971) -

Dec 29, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 6725558 (1984), 15008259 (2004)). -

Apr 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA1 c.43T>C; p.Trp15Arg variant (HB Evanston, also known as p.Trp14Arg when numbered from the mature protein, rs33964317, HbVar ID:16) has been reported in the compound heterozygous state in several individuals and families with phenotypes ranging from mild Hb H disease to microcytic anemia (Harteveld 2004, Honig 1984, Moo-Penn 1983, see HbVar and references therein). This variant is also reported in ClinVar (Variation ID: 439103), and is found in the general population with an overall allele frequency of 0.017% (28/166364 alleles) in the Genome Aggregation Database. The tryptophan at codon 15 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.705). Multiple functional assays show instability and skewed alpha/beta globin ratio when in-trans with other deletion alleles (Harteveld 2004 and Honig 1984). Based on available information, the p.Trp15Arg variant is considered to be likely pathogenic. References: Harteveld CL et al. A new Hb evanston allele [alpha14(A12)Trp --> Arg] found solely, and in the presence of common alpha-thalassemia deletions, in three independent Asian cases. Hemoglobin. 2004 Feb;28(1):1-5. PMID: 15008259. Honig GR et al. Hemoglobin Evanston (alpha 14 Trp----Arg). An unstable alpha-chain variant expressed as alpha-thalassemia. J Clin Invest. 1984 Jun;73(6):1740-9. PMID: 6725558. Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Moo-Penn WF et al. Hemoglobin Evanston: alpha 14(A12) Trp leads to Arg. A variant hemoglobin associated with alpha-thalassemia-2. Biochim Biophys Acta. 1983 Sep 14;747(1-2):65-70. PMID: 6882779. -

alpha Thalassemia

Pathogenic:2

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp15Arg variant in HBA1 (also known as HB Evanston) has been reported in several individuals with microcytosis (Honig 1984 PMID: 6725558, Harteveld 2004 MID: 15008259, https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=16). It has been reported in clinvar (Variation ID 439103) and was identified in 3/4792 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/variant). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies using patient samples support an impact on protein function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha thalassemia. ACMG/AMP Criteria applied: PM2_supporting, PM3_Strong, PS3_Supporting. -

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693798:Methemoglobinemia, alpha type;C4693823:Erythrocytosis, familial, 7

Pathogenic:1

Feb 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.44

Eigen

Benign

0.073

Eigen_PC

Benign

0.025

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.89

MetaRNN

Uncertain

0.72

MetaSVM

Pathogenic

0.98

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-13

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.78

MutPred

0.30

Gain of disorder (P = 0.0034);

MVP

1.0

ClinPred

0.98

GERP RS

4.5

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