rs374054030

Variant names:

• chr16-176693-C-G
• rs374054030
• NM_000558.5:c.-24C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-176693-C-G
• chr16-176693-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000558.5(HBA1):​c.-24C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 148,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (0 hom., cov: 29)
  • Exomes 𝑓: 0.063 (33 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.68
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-176693-C-G is Benign according to our data. Variant chr16-176693-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.-24C>G		5_prime_UTR	Exon 1 of 3	NP_000549.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA1	ENST00000320868.9	TSL:1 MANE Select	c.-24C>G		5_prime_UTR	Exon 1 of 3	ENSP00000322421.5
	HBA1	ENST00000875767.1		c.-24C>G		5_prime_UTR	Exon 1 of 3	ENSP00000545826.1
	ENSG00000294436	ENST00000723616.1		n.259G>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7404 AN: 148618 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0964

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0781

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.0723

Gnomad OTH AF: 0.0616

GnomAD2 exomes AF: 0.0519 AC: 12127 AN: 233582 AF XY: 0.0556

Gnomad AFR exome AF: 0.00861

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0651

Gnomad OTH exome AF: 0.0589

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0626 AC: 87247 AN: 1393904 Hom.: 33 Cov.: 32 AF XY: 0.0634 AC XY: 43926 AN XY: 692460

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

African (AFR) AF: 0.0112 AC: 369 AN: 33030

American (AMR) AF: 0.0330 AC: 1403 AN: 42458

Ashkenazi Jewish (ASJ) AF: 0.0999 AC: 2418 AN: 24206

East Asian (EAS) AF: 0.000228 AC: 9 AN: 39518

South Asian (SAS) AF: 0.0708 AC: 5741 AN: 81118

European-Finnish (FIN) AF: 0.0348 AC: 1786 AN: 51356

Middle Eastern (MID) AF: 0.0860 AC: 439 AN: 5102

European-Non Finnish (NFE) AF: 0.0676 AC: 71609 AN: 1059596

Other (OTH) AF: 0.0604 AC: 3473 AN: 57520

⚠️ 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: 0.0498 AC: 7401 AN: 148734 Hom.: 0 Cov.: 29 AF XY: 0.0481 AC XY: 3498 AN XY: 72784

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

African (AFR) AF: 0.0130 AC: 539 AN: 41340

American (AMR) AF: 0.0546 AC: 811 AN: 14862

Ashkenazi Jewish (ASJ) AF: 0.0964 AC: 317 AN: 3290

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5196

South Asian (SAS) AF: 0.0779 AC: 366 AN: 4696

European-Finnish (FIN) AF: 0.0358 AC: 373 AN: 10426

Middle Eastern (MID) AF: 0.114 AC: 32 AN: 280

European-Non Finnish (NFE) AF: 0.0724 AC: 4758 AN: 65726

Other (OTH) AF: 0.0605 AC: 124 AN: 2050

⚠️ 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: 0.0772 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.92
DANN	Benign	0.45
PhyloP100		-2.7
PromoterAI		0.26	Neutral
Mutation Taster		=300/0	polymorphism

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: rs374054030; hg19: chr16-226692; COSMIC: COSV108015498; COSMIC: COSV108015498;