16-173598-T-G

Position:

chr16-173598-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The NM_000517.6(HBA2):c.427T>G(p.Ter143Gluext*?) variant causes a stop lost change. The variant allele was found at a frequency of 0.00000435 in 1,608,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 25)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HBA2
NM_000517.6 stop_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 4.12

Variant links:

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) 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]

HBA2 links:

HBA2 (HGNC:):

HBA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM4

Stoplost variant in NM_000517.6 Downstream stopcodon found after 154 codons.

PP5

Variant 16-173598-T-G is Pathogenic according to our data. Variant chr16-173598-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.427T>G	p.Ter143Gluext*?	stop_lost	3/3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 linkuse as main transcript	c.427T>G	p.Ter143Gluext*?	stop_lost	3/3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000482565.1 linkuse as main transcript	n.563T>G		non_coding_transcript_exon_variant	2/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.331T>G	p.Ter111Gluext*?	stop_lost	3/3	2		ENSP00000380908.1	G3V1N2
ENSG00000290038	ENST00000702607.1 linkuse as main transcript	n.63A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000516

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459094

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725622

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149046

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72752

show subpopulations

Gnomad4 AFR

AF:

0.0000516

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2023	This protein extension has been observed in individual(s) with thalassemia (PMID: 9255612). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs41464951, gnomAD 0.01%). This sequence change disrupts the translational stop signal of the HBA2 mRNA. It is expected to extend the length of the HBA2 protein by 31 additional amino acid residues. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant results in an extension of the HBA2 protein. Other variant(s) that result in a similarly extended protein product (p.143Glnext31) have been determined to be pathogenic (PMID: 2298455, 4944483, 6725554, 9057661, 12393486, 20507641). This suggests that these extensions are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 15653). This variant is also known as Hb Seal Rock. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 09, 2024	The c.427T>G (p.143Gluext31) pathogenic variant leads to the replacement of the normal stop codon by a glutamic acid and extension of the alpha-globin chain by 31 amino acids (p.143Gluext31). Individuals positive for this variant and the -alpha3.7 deletion have a clinical presentation that is comparable to that of mild Hb H disease (see Hb Var (http://globin.cse.psu.edu/cgi-bin/hbvar/counter) and PMID: 9255612 (1997)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 05, 2021	The Hb Seal Rock variant (HBA2: c.427T>G; p.Ter143Glu, also known as Ter142Glu when numbered from the mature protein, rs41464951) is described in the literature in individuals with HbH disease who carry alpha globin deletions on the opposite chromosome (Das 2014, Merritt 1997, see HbVar link). This variant is reported in ClinVar (Variation ID: 15653), and found in the general population with a low overall allele frequency of 0.003% (1/30200 alleles) in the Genome Aggregation Database. This variant abolishes the canonical termination codon, resulting in an elongated protein that is unstable, similar to other stop loss variants (Hb Constant Spring, Hb Icaria)(see HbVar links and references therein). Based on available information, the Hb Seal Rock variant is considered to be pathogenic. References: Link to HbVar database for Hb Constant Spring: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=703&.cgifields=histD Link to HbVar database for Hb Icaria: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=704&.cgifields=histD Link to HbVar database for Hb Seal Rock: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=706&.cgifields=histD Das R et al. Wide Spectrum of Molecular and Clinical Heterogeneity in HbH Disease in North Indian Patients. Blood 124.21 (2014): 1358. Web. 21 Aug. 2018. Merritt D et al. Hb Seal Rock ((alpha 2)142 term-->Glu, codon 142 TAA-->GAA): an extended alpha chain variant associated with anemia, microcytosis, and alpha-thalassemia-2 (-3.7 Kb). Hemoglobin. 1997 Jul;21(4):331-44. -

alpha Thalassemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

HEMOGLOBIN SEAL ROCK

Other:1

other, no assertion criteria provided

literature only

OMIM

May 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0077

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.84

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

Vest4

0.16

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

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