16-173175-T-G

Variant names:

• chr16-173175-T-G
• rs41392146
• NM_000517.6:c.146T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000517.6(HBA2):​c.146T>G​(p.Leu49Arg) 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 Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.000010 (0 hom., cov: 12)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:2
• Conservation: PhyloP100: 2.43
• 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, ClinGen, 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
• unstable hemoglobin disease

  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 3 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, 0.911

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.146T>G	p.Leu49Arg	missense	Exon 2 of 3	NP_000508.1	D1MGQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.146T>G	p.Leu49Arg	missense	Exon 2 of 3	ENSP00000251595.6	P69905
	HBA2	ENST00000484216.1	TSL:1	c.113T>G	p.Leu38Arg	missense	Exon 2 of 2	ENSP00000495899.1	A0A2R8Y7C0
	HBA2	ENST00000482565.1	TSL:1	n.282T>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00000998 AC: 1 AN: 100234 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.0000561

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 Cov.: 11

GnomAD4 genome AF: 0.00000998 AC: 1 AN: 100234 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 47508

African (AFR) AF: 0.0000561 AC: 1 AN: 17836

American (AMR) AF: 0.00 AC: 0 AN: 10356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2812

East Asian (EAS) AF: 0.00 AC: 0 AN: 3690

South Asian (SAS) AF: 0.00 AC: 0 AN: 2296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53688

Other (OTH) AF: 0.00 AC: 0 AN: 1256

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	alpha Thalassemia (1)
-	1	-	not specified (1)
-	-	-	HEMOGLOBIN BIRMINGHAM (USA) (1)
-	-	-	HEMOGLOBIN MONTGOMERY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.98	D
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Vest4		0.44
MutPred		0.90		Gain of solvent accessibility (P = 0.0156)
MVP		1.0
MPC		2.3
ClinPred		0.98	D
GERP RS		4.2
PromoterAI		0.0060	Neutral
gMVP		0.94
Mutation Taster		=21/79	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: rs41392146; hg19: chr16-223174;