rs35317336

Positions:

• chr16-176996-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 6P and 8B. PM2 PP3_Strong BP6_Very_Strong

The NM_000558.5(HBA1):​c.163C>G​(p.Gln55Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q55R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:5
• Conservation: PhyloP100: -0.244

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• BP6: Variant 16-176996-C-G is Benign according to our data. Variant chr16-176996-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 15782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5	c.163C>G	p.Gln55Glu	missense_variant	2/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.163C>G	p.Gln55Glu	missense_variant	2/3	1	NM_000558.5	ENSP00000322421.5
HBA1	ENST00000472694.1	n.299C>G		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1	n.132C>G		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1	c.67C>G	p.Gln23Glu	missense_variant	2/3	2		ENSP00000380899.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 31

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 15, 2021	- -

HEMOGLOBIN J (MEXICO) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

HEMOGLOBIN MEXICO Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

HEMOGLOBIN J (PARIS 2) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

HEMOGLOBIN UPPSALA Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

HEMOGLOBIN J 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	0.13
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.044	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.14	T;T
Vest4		0.59
MutPred		0.87		Loss of methylation at K57 (P = 0.0824);.;
MVP		0.99
ClinPred		0.51	D
GERP RS		2.2
Varity_R		0.80
gMVP		0.82

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: rs35317336; hg19: chr16-226995;