rs41417548

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000517.6(HBA2):c.314G>A(p.Cys105Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C105R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 0.402

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000517.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-173484-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 804215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 16-173485-G-A is Pathogenic according to our data. Variant chr16-173485-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.314G>A	p.Cys105Tyr	missense_variant	3/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11 linkuse as main transcript	c.314G>A	p.Cys105Tyr	missense_variant	3/3	1	NM_000517.6	P1
	ENST00000702607.1 linkuse as main transcript			downstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

248070

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134572

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:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1458220

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725242

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:

0.000106

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	HBA2: PM3:Very Strong, PM2, PP1:Moderate, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 09, 2021	The Hb Sallanches variant (HBA2: c.314G>A; p.Cys105Tyr, also known as Cys104Tyr when numbered from the mature protein, rs41417548) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals with Hb H disease (Hb Var and references therein, Sharma 2020). Functional analyses show the variant protein is unstable and display a defect in binding with alpha-hemoglobin stabilizing protein (Sharma 2020, Wajcman 2011). This variant is reported in ClinVar (Variation ID: 15656). This variant is found in the South Asian population with an allele frequency of 0.017% (5/30278 alleles) in the Genome Aggregation Database. The cysteine at codon 105 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.678). Based on available information, this variant is considered to be likely pathogenic. References: Hb Var for Hb Sallanches: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=167&.cgifields=histD Sharma P et al. HbH disease due to compound heterozygosity for hemoglobins Zürich-Albisrieden and Sallanches. Pediatr Blood Cancer. 2020 Apr;67(4):e28161. PMID: 31930682. Wajcman H et al. a-Hemoglobin stabilizing protein: a modulating factor in thalassemias? Hemoglobin. 2011;35(5-6):463-8. PMID: 21950764. -

alpha Thalassemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with [GeneName] related disorder (ClinVar ID: VCV000015656, PMID:8555062). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10722113). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000804215, PMID:23181747). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.678>=0.6). A missense variant is a common mechanism . Itis observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000202). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Hemoglobin H disease, nondeletional

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2000

- -

Hemoglobin H disease

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Breakthrough Genomics, Breakthrough Genomics

This variant (also known as Hb Sallanches variant; Cys104Tyr) has been previously reported multiple individuals with Hemoglobin H disease in homozygous state [PMID: 11186268, 8555062, 10722113, 20113287]. Functional analyses showed the variant protein is unstable and display a defect in binding with alpha-hemoglobin stabilizing protein [31930682, 21950764]. -

HEMOGLOBIN SALLANCHES

Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T

Eigen

Benign

0.18

Eigen_PC

Benign

-0.0083

FATHMM_MKL

Benign

0.31

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.80

MutationTaster

Benign

0.96

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-9.1

D;D

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.022

D;D

Vest4

0.79

MutPred

0.92

Loss of stability (P = 0.134);.;

MVP

1.0

MPC

3.2

ClinPred

0.98

GERP RS

0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.95

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