rs35932809

Positions:

• chr16-177332-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_000558.5(HBA1):​c.350A>C​(p.Glu117Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.70

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37924984).
• BP6: Variant 16-177332-A-C is Benign according to our data. Variant chr16-177332-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 15832.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5	c.350A>C	p.Glu117Ala	missense_variant	3/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.350A>C	p.Glu117Ala	missense_variant	3/3	1	NM_000558.5	ENSP00000322421	P1
HBA1	ENST00000472694.1	n.486A>C		non_coding_transcript_exon_variant	2/2	1
	ENST00000702457.1	n.159T>G		non_coding_transcript_exon_variant	1/1
HBA1	ENST00000397797.1	c.254A>C	p.Glu85Ala	missense_variant	3/3	2		ENSP00000380899

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246936 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 08, 2021

- -

HEMOGLOBIN UBE-4 Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.047	D;D
Sift4G	Benign	0.092	T;T
Vest4		0.14
MutPred		0.42		Loss of solvent accessibility (P = 0.0404);.;
MVP		1.0
ClinPred		0.18	T
GERP RS		4.3
Varity_R		0.40
gMVP		0.79

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: rs35932809; hg19: chr16-227331;