16-173384-T-G

Position:

• chr16-173384-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000484216.1(HBA2):​c.325T>G​(p.Ser109Ala) 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:5
• Conservation: PhyloP100: 0.430

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]

ACMG classification

Verdict is Benign. Variant got -20 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 [Likely_benign]. Clinvar id is 439769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0188 (2711/144308) while in subpopulation AFR AF= 0.0388 (1335/34402). AF 95% confidence interval is 0.0371. There are 193 homozygotes in gnomad4. There are 1363 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 193 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.300+55T>G		intron_variant		ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000484216.1	c.325T>G	p.Ser109Ala	missense_variant	2/2	1
HBA2	ENST00000251595.11	c.300+55T>G		intron_variant		1	NM_000517.6	P1
HBA2	ENST00000482565.1	n.436+55T>G		intron_variant, non_coding_transcript_variant		1
HBA2	ENST00000397806.1	c.204+55T>G		intron_variant		2

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

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.00672

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.0127

Gnomad4 SAS exome AF: 0.0209

Gnomad4 FIN exome AF: 0.0160

Gnomad4 NFE exome AF: 0.00782

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0188 AC: 2711 AN: 144308 Hom.: 193 Cov.: 25 AF XY: 0.0193 AC XY: 1363 AN XY: 70598

Gnomad4 AFR AF: 0.0388

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.0124

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.0197 Hom.: 30

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2020	- -

alpha Thalassemia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

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