16-177078-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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]

ENSG00000290010 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 14 uncertain in NM_000558.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• BS2: High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.245C>G	p.Ser82Cys	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.245C>G	p.Ser82Cys	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000476 AC: 7 AN: 147032 Hom.: 0 AF XY: 0.0000623 AC XY: 5 AN XY: 80276

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 SAS exome AF: 0.000297

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

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Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.81	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.037	D;T
Vest4		0.54
MutPred		0.80		Loss of disorder (P = 0.0063);.;
MVP		1.0
ClinPred		0.72	D
GERP RS		3.3
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

Publications

LitVar

Other links and lift over

dbSNP: rs34936612; hg19: chr16-227077;