rs33957286

chr11-5225656-G-Achr11-5225656-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000518.5(HBB):c.386C>T(p.Ala129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A129D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 0.0730

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [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 5 benign, 15 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225656-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.386C>T	p.Ala129Val	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.386C>T	p.Ala129Val	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.386C>T	p.Ala129Val	missense_variant	3/3			P1
HBB	ENST00000475226.1	n.318C>T		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*202C>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 17, 2023

Variant summary: HBB c.386C>T (p.Ala129Val) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251300 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.386C>T has been reported in the literature as Hb Sitia [beta128(H6)Ala-->Val] in a Greek female with slightly reduced red blood cell indices, mild instability of the molecule and slight modifications of the oxygen binding properties (Papassotiriou_2001). These report(s) do not provide unequivocal conclusions about association of the variant with Beta Thalassemia or Hemoglobinopathy. To our knowledge, no conclusive experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

HEMOGLOBIN SITIA Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.55	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0050	D;.
Sift4G	Benign	0.14	T;.
Polyphen		0.32	B;B
Vest4		0.77
MutPred		0.67		Gain of stability (P = 0.0955);Gain of stability (P = 0.0955);
MVP		0.80
MPC		0.038
ClinPred		0.90	D
GERP RS		1.8
Varity_R		0.27
gMVP		0.86

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: rs33957286; hg19: chr11-5246886;