16-177095-C-T

Position:

• chr16-177095-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000558.5(HBA1):​c.262C>T​(p.His88Tyr) variant causes a missense change. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H88N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:4
• Conservation: PhyloP100: 5.42

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-177095-C-T is Pathogenic according to our data. Variant chr16-177095-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15779.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.262C>T	p.His88Tyr	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.262C>T	p.His88Tyr	missense_variant	2/3	1	NM_000558.5	ENSP00000322421.5
HBA1	ENST00000472694.1	n.398C>T		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1	n.231C>T		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1	c.166C>T	p.His56Tyr	missense_variant	2/3	2		ENSP00000380899.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1402412 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 695534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:4

Revision: criteria provided, single submitter

Submissions by phenotype

Methemoglobinemia, alpha type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

-

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with HBA1 related disorder (PMID: 10477710). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10477710, 3957697, 6998928). Different missense changes at the same codon (p.His88Asp, p.His88Gln, p.His88Pro) have been reported to be associated with HBA1 related disorder (ClinVar ID: VCV001809522 / PMID: 18310146, 27225845). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

HEMOGLOBIN M (KANKAKEE) Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

HEMOGLOBIN M (IWATE) Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

HEMOGLOBIN M (OLDENBURG) Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

HEMOGLOBIN M (SENDAI) Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.86
MutPred		0.99		Loss of disorder (P = 0.0404);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.97
gMVP		0.99

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: rs28928876; hg19: chr16-227094;