NM_000517.6:c.154G>C

Variant names:

• chr16-173183-G-C
• rs281864837
• NM_000517.6:c.154G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PP3_Strong BP6_Moderate

The NM_000517.6(HBA2):​c.154G>C​(p.Gly52Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.08
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_000517.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• BP6: Variant 16-173183-G-C is Benign according to our data. Variant chr16-173183-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1330698.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.154G>C	p.Gly52Arg	missense	Exon 2 of 3	NP_000508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.154G>C	p.Gly52Arg	missense	Exon 2 of 3	ENSP00000251595.6
	HBA2	ENST00000484216.1	TSL:1	c.121G>C	p.Gly41Arg	missense	Exon 2 of 2	ENSP00000495899.1
	HBA2	ENST00000482565.1	TSL:1	n.290G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD2 exomes AF: 0.0000155 AC: 2 AN: 129086 AF XY: 0.0000286

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000394

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000352 AC: 3 AN: 851442 Hom.: 0 Cov.: 12 AF XY: 0.00000684 AC XY: 3 AN XY: 438738

African (AFR) AF: 0.00 AC: 0 AN: 17900

American (AMR) AF: 0.00 AC: 0 AN: 36052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21582

East Asian (EAS) AF: 0.00 AC: 0 AN: 33688

South Asian (SAS) AF: 0.00 AC: 0 AN: 67992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2926

European-Non Finnish (NFE) AF: 0.00000502 AC: 3 AN: 597190

Other (OTH) AF: 0.00 AC: 0 AN: 39646

GnomAD4 genome Cov.: 13

ExAC AF: 0.0000204 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 11, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.78	D
PhyloP100		2.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.088	T
Vest4		0.53
MutPred		0.96		Gain of solvent accessibility (P = 0.019)
MVP		0.99
MPC		2.7
ClinPred		0.90	D
GERP RS		4.2
PromoterAI		0.0076	Neutral
gMVP		0.85
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs281864837; hg19: chr16-223182;