rs63750776

Positions:

• chr16-173135-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Moderate PP5_Moderate

The NM_000517.6(HBA2):​c.106T>C​(p.Ser36Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 10)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -1.10

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) 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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000517.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 16-173135-T-C is Pathogenic according to our data. Variant chr16-173135-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 993102.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.106T>C	p.Ser36Pro	missense_variant	2/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.106T>C	p.Ser36Pro	missense_variant	2/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1	c.76T>C	p.Ser26Pro	missense_variant	2/2	1
HBA2	ENST00000482565.1	n.242T>C		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.10T>C	p.Ser4Pro	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 8

GnomAD4 genome Cov.: 10

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 13, 2021

The variant has been reported as a variant having an alpha thalassemia-like phenotype. It has been observed in heterozygous carriers from a Portuguese family and associated with moderate erythrocytosis, microcytosis, and hypochromia (PMID: 17296578 (2007)). This variant was described as being unstable and causing Hb H disease in a severely affected infant with the Filipino deletional mutation (--FIL) on the other allele (PMID: 11722414 (2001)). This variant has not been reported in large, multi-ethnic general populations. -

HEMOGLOBIN H HYDROPS FETALIS SYNDROME Other:1

other, no assertion criteria provided

literature only

OMIM

Oct 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.082	.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.042	N
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.33	D
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.088	T;T
Vest4		0.62
MutPred		0.78		Gain of glycosylation at T39 (P = 0.1011);.;
MVP		0.99
MPC		2.6
ClinPred		0.90	D
GERP RS		-8.3
gMVP		0.95

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: rs63750776; hg19: chr16-223134;