NM_000517.6:c.420A>C

Variant names:

• chr16-173591-A-C
• rs41393644
• NM_000517.6:c.420A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000517.6(HBA2):​c.420A>C​(p.Lys140Asn) 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 other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K140E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.418
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Heinz body anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000517.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-173589-A-G is described in ClinVar as Pathogenic|other. ClinVar VariationId is 15646.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.420A>C	p.Lys140Asn	missense	Exon 3 of 3	NP_000508.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.420A>C	p.Lys140Asn	missense	Exon 3 of 3	ENSP00000251595.6
	HBA2	ENST00000482565.1	TSL:1	n.556A>C		non_coding_transcript_exon	Exon 2 of 2
	HBA2	ENST00000866237.1		c.336A>C	p.Lys112Asn	missense	Exon 3 of 3	ENSP00000536296.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1458928 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725556

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32180

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 85198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111748

Other (OTH) AF: 0.00 AC: 0 AN: 60254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions as Germline

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	HEMOGLOBIN FUKUI (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.86	D
PhyloP100		0.42
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.68
MutPred		0.83		Loss of MoRF binding (P = 0.0177)
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
gMVP		0.81
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs41393644; hg19: chr16-223590;