16-176999-G-C

Position:

• chr16-176999-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000558.5(HBA1):​c.166G>C​(p.Val56Leu) 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 other (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.0380

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5	c.166G>C	p.Val56Leu	missense_variant	2/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA1	ENST00000320868.9	c.166G>C	p.Val56Leu	missense_variant	2/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1	n.302G>C		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1	n.135G>C		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1	c.70G>C	p.Val24Leu	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 31

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN ROUBAIX 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	0.32
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	7.5
DANN	Benign	0.83
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.86	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.44	T;T
Vest4		0.65
MutPred		0.85		Loss of methylation at K57 (P = 0.0343);.;
MVP		1.0
ClinPred		0.30	T
GERP RS		-5.1
Varity_R		0.50
gMVP		0.81

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: rs34068598; hg19: chr16-226998;