rs41328049

Variant names:

• chr16-173207-G-C
• rs41328049
• NM_000517.6:c.178G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-173207-G-C
• chr16-173207-G-A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000517.6(HBA2):​c.178G>C​(p.Gly60Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004563528: The amino acid substitution involves the glycine residue at a structurally critical position significantly affecting the stability of the hemoglobin (Dutly 2004, Scheps 2020, Sharma 2020). PMID:15658192. PMID:31553106. PMID:31930682.". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G60D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000078 (1 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.54
• Publications: 3 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004563528: The amino acid substitution involves the glycine residue at a structurally critical position significantly affecting the stability of the hemoglobin (Dutly 2004, Scheps 2020, Sharma 2020). PMID: 15658192. PMID: 31553106. PMID: 31930682.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 12 uncertain in NM_000517.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-173208-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 439112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 16-173207-G-C is Pathogenic according to our data. Variant chr16-173207-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 15688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.178G>C	p.Gly60Arg	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.178G>C	p.Gly60Arg	missense	Exon 2 of 3	ENSP00000251595.6	P69905
	HBA2	ENST00000484216.1	TSL:1	c.145G>C	p.Gly49Arg	missense	Exon 2 of 2	ENSP00000495899.1	A0A2R8Y7C0
	HBA2	ENST00000482565.1	TSL:1	n.314G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD2 exomes AF: 0.0000305 AC: 4 AN: 131276 AF XY: 0.0000564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000941

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000784 AC: 8 AN: 1019914 Hom.: 1 Cov.: 14 AF XY: 0.0000116 AC XY: 6 AN XY: 517672

African (AFR) AF: 0.00 AC: 0 AN: 20172

American (AMR) AF: 0.00 AC: 0 AN: 35680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22734

East Asian (EAS) AF: 0.0000292 AC: 1 AN: 34224

South Asian (SAS) AF: 0.0000988 AC: 7 AN: 70838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 753766

Other (OTH) AF: 0.00 AC: 0 AN: 45100

GnomAD4 genome Cov.: 17

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000107 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	alpha Thalassemia (1)
1	-	-	Alpha-thalassemia, Dutch type (1)
1	-	-	not provided (1)
-	-	-	HEMOGLOBIN ZURICH ALBISRIEDEN (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.84
MutPred		0.98		Gain of MoRF binding (P = 0.0338)
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		0.0097	Neutral
gMVP		0.98
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41328049; hg19: chr16-223206;