rs33949486

Positions:

• chr11-5225632-C-G
• chr11-5225632-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_000518.5(HBB):​c.410G>C​(p.Gly137Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225632-C-T is described in Lovd as [Pathogenic].
• PP5: Variant 11-5225632-C-G is Pathogenic according to our data. Variant chr11-5225632-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.31439036). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.410G>C	p.Gly137Ala	missense_variant	3/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.410G>C	p.Gly137Ala	missense_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1	c.410G>C	p.Gly137Ala	missense_variant	3/3			ENSP00000494175	P1
HBB	ENST00000633227.1	c.*226G>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000488004
HBB	ENST00000475226.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.83	.;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.83	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.2	N;.
REVEL	Uncertain	0.41
Sift	Benign	0.055	T;.
Sift4G	Benign	0.80	T;.
Polyphen		0.47	P;P
Vest4		0.31
MutPred		0.59		Loss of catalytic residue at A136 (P = 0.0623);Loss of catalytic residue at A136 (P = 0.0623);
MVP		0.68
MPC		0.046
ClinPred		0.29	T
GERP RS		4.7
Varity_R		0.33
gMVP		0.67

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: rs33949486; hg19: chr11-5246862;