11-5225679-T-G

Position:

• chr11-5225679-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000518.5(HBB):​c.363A>C​(p.Lys121Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K121E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: -1.12

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]

HBB (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13290045).
• BP6: Variant 11-5225679-T-G is Benign according to our data. Variant chr11-5225679-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15329.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.363A>C	p.Lys121Asn	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.363A>C	p.Lys121Asn	missense_variant	3/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251288 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2016	Variant summary: The HBB c.363A>C (p.Lys121Asn) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was not found in 121384 control chromosomes in the ExAC database; however, it was found in 4/552 control chromsomes in the Indian population at a frequency of 0.00725. Although this frequency does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803), all 4 alleles were from two healthy individuals whom were homozygous for the variant of interest, suggesting that it is unlikely to be pathogenic. Although this variant was also found in two individuals who were compound heterozygous for this variant and another BTHAL-0 variant, the subjects had BTHAL MINOR, suggesting the variant is clinically silent (Pinkerton_1979 and Hirsch_1997). The variant has also been found in patients with alpha-thalassemia and iron deficiency, renal calculi, diabetes mellitues and hypertension; the variety of observed phenotypes suggests that the variant is not associated with hemoglobinopathy. Although this variant has been shown to significantly delay crystallization of hemolysate (Hirsch_1997), its functional role in hemoglobinopathy is not clear. OMIM classified this variant as pathogenic, however, this classification has not been updated since 1979 and could be questionable. Taken together, this variant is classified as VUS-possibly benign variant. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2020	This variant is also known as Hb Riyadh (PMID: 1052171 (1976)) and Hb Karatsu (PMID: 893141 (1977)). In the published literature, homozygous asymptomatic persons from India (PMID: 24099628 (2014)) and asymptomatic heterozygous persons from Mexican and Japanese families have been identified (PMID: 893129 (1977), 893141 (1977), and Hidaka and Iuchi (1986) Kawasaki Med J 12(3):149). It was originally described in a Saudi Arabian woman who was likely also to have alpha thalassemia (PMID: 1052171 (1976)). Not long after, this variant was described in a woman from India who also carried a beta-0-thalassemia mutation but only showed a simple beta-thalassemia trait and no clinical effects (PMID: 511584 (1979)). Functional studies show this variant has normal stability (PMID: 893129 (1977) and 893141 (1977)) and normal oxygen affinity (PMID: 893129 (1977)). -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2023	- -

not specified Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1979

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	11
DANN	Benign	0.84
DEOGEN2	Benign	0.079	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.82	.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.40
Sift	Benign	0.041	D;.
Sift4G	Benign	0.13	T;.
Polyphen		0.0070	B;B
Vest4		0.42
MutPred		0.43		Loss of methylation at K121 (P = 7e-04);Loss of methylation at K121 (P = 7e-04);
MVP		0.91
MPC		0.037
ClinPred		0.032	T
GERP RS		-2.0
Varity_R		0.28
gMVP		0.55

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: rs34726542; hg19: chr11-5246909;