rs2362746

Variant names:

• chr16-173384-T-G
• rs2362746
• ENST00000484216.1:c.322T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000484216.1(HBA2):​c.322T>G​(p.Ser108Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 144,308 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (193 hom., cov: 25)
  • Exomes 𝑓: 0.0097 (623 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 ENST00000484216.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.430
• Publications: 4 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-173384-T-G is Benign according to our data. Variant chr16-173384-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 193 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000484216.1. 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.300+55T>G		intron	N/A	NP_000508.1	D1MGQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000484216.1	TSL:1	c.322T>G	p.Ser108Ala	missense	Exon 2 of 2	ENSP00000495899.1	A0A2R8Y7C0
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.300+55T>G		intron	N/A	ENSP00000251595.6	P69905
	HBA2	ENST00000482565.1	TSL:1	n.436+55T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2685 AN: 144214 Hom.: 186 Cov.: 25

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.0268

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.0161

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0153

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00969 AC: 13970 AN: 1441300 Hom.: 623 Cov.: 32 AF XY: 0.0100 AC XY: 7177 AN XY: 716920

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

African (AFR) AF: 0.0369 AC: 1055 AN: 28590

American (AMR) AF: 0.00672 AC: 296 AN: 44036

Ashkenazi Jewish (ASJ) AF: 0.00597 AC: 155 AN: 25956

East Asian (EAS) AF: 0.0127 AC: 503 AN: 39558

South Asian (SAS) AF: 0.0209 AC: 1737 AN: 83228

European-Finnish (FIN) AF: 0.0160 AC: 843 AN: 52712

Middle Eastern (MID) AF: 0.0130 AC: 66 AN: 5060

European-Non Finnish (NFE) AF: 0.00782 AC: 8626 AN: 1102960

Other (OTH) AF: 0.0116 AC: 689 AN: 59200

⚠️ 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 AF: 0.0188 AC: 2711 AN: 144308 Hom.: 193 Cov.: 25 AF XY: 0.0193 AC XY: 1363 AN XY: 70598

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

African (AFR) AF: 0.0388 AC: 1335 AN: 34402

American (AMR) AF: 0.0127 AC: 190 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 26 AN: 3468

East Asian (EAS) AF: 0.0124 AC: 64 AN: 5156

South Asian (SAS) AF: 0.0269 AC: 124 AN: 4602

European-Finnish (FIN) AF: 0.0173 AC: 184 AN: 10620

Middle Eastern (MID) AF: 0.0139 AC: 4 AN: 288

European-Non Finnish (NFE) AF: 0.0111 AC: 751 AN: 67840

Other (OTH) AF: 0.0157 AC: 32 AN: 2042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0197 Hom.: 30

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	alpha Thalassemia (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.31
PhyloP100		0.43
PromoterAI		-0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2362746; hg19: chr16-223383; COSMIC: COSV52406474; COSMIC: COSV52406474;