chr16-177078-C-G

Variant names:

• chr16-177078-C-G
• rs34936612
• NM_000558.5:c.245C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PP3_Moderate BS2

The NM_000558.5(HBA1):​c.245C>G​(p.Ser82Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,386,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (2 hom.)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.883
• 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):

• alpha thalassemia spectrum

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 30 uncertain in NM_000558.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA1	NM_000558.5	MANE Select	c.245C>G	p.Ser82Cys	missense	Exon 2 of 3	NP_000549.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA1	ENST00000320868.9	TSL:1 MANE Select	c.245C>G	p.Ser82Cys	missense	Exon 2 of 3	ENSP00000322421.5
	HBA1	ENST00000472694.1	TSL:1	n.381C>G		non_coding_transcript_exon	Exon 1 of 2
	HBA1	ENST00000487791.1	TSL:1	n.214C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000476 AC: 7 AN: 147032 AF XY: 0.0000623

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1386962 Hom.: 2 Cov.: 26 AF XY: 0.0000160 AC XY: 11 AN XY: 687634

African (AFR) AF: 0.00 AC: 0 AN: 31960

American (AMR) AF: 0.00 AC: 0 AN: 38288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25266

East Asian (EAS) AF: 0.00 AC: 0 AN: 37162

South Asian (SAS) AF: 0.000172 AC: 14 AN: 81484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4060

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074520

Other (OTH) AF: 0.00 AC: 0 AN: 57918

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000177 AC: 2

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN NIGERIA Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.81	D
PhyloP100		0.88
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.037	D
Vest4		0.54
MutPred		0.80		Loss of disorder (P = 0.0063)
MVP		1.0
ClinPred		0.72	D
GERP RS		3.3
PromoterAI		-0.035	Neutral
Varity_R		0.83
gMVP		0.90

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: rs34936612; hg19: chr16-227077;