rs141514155

chr16-177457-C-Achr16-177457-C-T

Variant summary

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

The NM_000558.5(HBA1):c.*46C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,603,218 control chromosomes in the GnomAD database, including 242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 32)
  • Exomes 𝑓: 0.013 (225 hom.)
• Consequence: HBA1 NM_000558.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0720

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-177457-C-A is Benign according to our data. Variant chr16-177457-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 439094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0117 (1789/152288) while in subpopulation SAS AF= 0.0178 (86/4826). AF 95% confidence interval is 0.0148. There are 17 homozygotes in gnomad4. There are 933 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5	c.*46C>A		3_prime_UTR_variant	3/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA1	ENST00000320868.9	c.*46C>A		3_prime_UTR_variant	3/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1	n.611C>A		non_coding_transcript_exon_variant	2/2	1
	ENST00000702457.1	n.34G>T		non_coding_transcript_exon_variant	1/1
HBA1	ENST00000397797.1	c.*46C>A		3_prime_UTR_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1788 AN: 152168 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0148 AC: 3410 AN: 230802 Hom.: 51 AF XY: 0.0152 AC XY: 1897 AN XY: 125086

Gnomad AFR exome AF: 0.00183

Gnomad AMR exome AF: 0.00516

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.0000582

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0135 AC: 19522 AN: 1450930 Hom.: 225 Cov.: 31 AF XY: 0.0140 AC XY: 10076 AN XY: 720950

Gnomad4 AFR exome AF: 0.00195

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.0394

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0345

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0117 AC: 1789 AN: 152288 Hom.: 17 Cov.: 32 AF XY: 0.0125 AC XY: 933 AN XY: 74492

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00622

Gnomad4 ASJ AF: 0.0424

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.0343

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0132 Hom.: 6

Bravo AF: 0.00852

Asia WGS AF: 0.00811 AC: 28 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

alpha Thalassemia Benign:2

Benign, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 09, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	2.9
Dann	Benign	0.64

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: rs141514155; hg19: chr16-227456;