rs36008624

Positions:

• chr16-177377-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000558.5(HBA1):​c.395C>T​(p.Ser132Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S132P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.901

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000558.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5	c.395C>T	p.Ser132Phe	missense_variant	3/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA1	ENST00000320868.9	c.395C>T	p.Ser132Phe	missense_variant	3/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1	n.531C>T		non_coding_transcript_exon_variant	2/2	1
	ENST00000702457.1	n.114G>A		non_coding_transcript_exon_variant	1/1
HBA1	ENST00000397797.1	c.299C>T	p.Ser100Phe	missense_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.025	D;D
Vest4		0.30
MutPred		0.69		Loss of disorder (P = 0.0429);.;
MVP		0.89
ClinPred		0.69	D
GERP RS		-8.3
Varity_R		0.40
gMVP		0.91

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: rs36008624; hg19: chr16-227376;