rs141514155

Variant names:

• chr16-177457-C-A
• rs141514155
• NM_000558.5:c.*46C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-177457-C-A
• chr16-177457-C-T

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: -0.0720
• Publications: 2 publications found

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]

HBA1 Gene-Disease associations (from GenCC):

• HBA1-related alpha thalassemia spectrum

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• alpha thalassemia spectrum

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen
• unstable hemoglobin disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Heinz body anemia

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000294436 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000558.5. 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
	HBA1	NM_000558.5	MANE Select	c.*46C>A		3_prime_UTR	Exon 3 of 3	NP_000549.1	P69905

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA1	ENST00000320868.9	TSL:1 MANE Select	c.*46C>A		3_prime_UTR	Exon 3 of 3	ENSP00000322421.5	P69905
	HBA1	ENST00000472694.1	TSL:1	n.611C>A		non_coding_transcript_exon	Exon 2 of 2
	HBA1	ENST00000875767.1		c.*46C>A		3_prime_UTR	Exon 3 of 3	ENSP00000545826.1

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

GnomAD2 exomes AF: 0.0148 AC: 3410 AN: 230802 AF XY: 0.0152

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 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

African (AFR) AF: 0.00195 AC: 65 AN: 33286

American (AMR) AF: 0.00569 AC: 247 AN: 43420

Ashkenazi Jewish (ASJ) AF: 0.0394 AC: 1020 AN: 25882

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39282

South Asian (SAS) AF: 0.0204 AC: 1732 AN: 84876

European-Finnish (FIN) AF: 0.0345 AC: 1788 AN: 51854

Middle Eastern (MID) AF: 0.0264 AC: 152 AN: 5758

European-Non Finnish (NFE) AF: 0.0123 AC: 13629 AN: 1106588

Other (OTH) AF: 0.0148 AC: 887 AN: 59984

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

African (AFR) AF: 0.00214 AC: 89 AN: 41580

American (AMR) AF: 0.00622 AC: 95 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4826

European-Finnish (FIN) AF: 0.0343 AC: 364 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 973 AN: 68018

Other (OTH) AF: 0.0128 AC: 27 AN: 2104

Alfa AF: 0.0132 Hom.: 6

Bravo AF: 0.00852

Asia WGS AF: 0.00811 AC: 28 AN: 3468

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	alpha Thalassemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.9
DANN	Benign	0.64
PhyloP100		-0.072
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: rs141514155; hg19: chr16-227456;