16-176967-C-T

Position:

• chr16-176967-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000558.5(HBA1):​c.134C>T​(p.Pro45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000955 in 1,046,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P45R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 9.6e-7 (0 hom.)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.683

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-176967-C-T is Pathogenic according to our data. Variant chr16-176967-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15783.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.134C>T	p.Pro45Leu	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.134C>T	p.Pro45Leu	missense_variant	2/3	1	NM_000558.5	ENSP00000322421	P1
HBA1	ENST00000472694.1	n.270C>T		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1	n.103C>T		non_coding_transcript_exon_variant	2/2	1
HBA1	ENST00000397797.1	c.38C>T	p.Pro13Leu	missense_variant	2/3	2		ENSP00000380899

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 9.55e-7 AC: 1 AN: 1046752 Hom.: 0 Cov.: 14 AF XY: 0.00000188 AC XY: 1 AN XY: 532460

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: 0.00000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 16, 2021

The Hb Milledgeville variant (HBA1: c.134C>T; p.Pro45Leu, also known as Pro44Leu when numbered from the mature protein, rs33978134) has been found heterozygous in multiple individuals with mild erythrocytosis (see link to HbVar and references therein). This variant has been reported to have increased oxygen affinity with reduced cooperativity. This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 45 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.544). Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar for Hb Milledgeville: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=57&.cgifields=histD -

Erythrocytosis, familial, 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 16, 1980

- -

HEMOGLOBIN MILLEDGEVILLE Other:1

other, no assertion criteria provided

literature only

OMIM

Nov 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.85	T;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.54	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.076	T;T
Vest4		0.47
MutPred		0.29		Loss of methylation at K41 (P = 0.0812);.;
MVP		0.98
ClinPred		0.97	D
GERP RS		2.3
Varity_R		0.51
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33978134; hg19: chr16-226966;