11-5225679-T-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:2

Conservation

PhyloP100: -1.12

Variant links:

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 links:

ENSG00000285498 (HGNC:):

ENSG00000285498 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.363A>C	p.Lys121Asn	missense_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.363A>C	p.Lys121Asn	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251288

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135796

show subpopulations

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:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

show subpopulations

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.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Sep 28, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Riyadh variant (HBB: c.363A>C; p.Lys121Asn, also known as Lys120Asn when numbered from the mature protein, rs34726542, HbVar ID: 506) has been reported in several healthy individuals (HbVar database and references therein), and in the ClinVar database (Variation ID: 15329). The variant protein exhibits normal stability and oxygen affinity, and had no deleterious impact in the presence of a beta-0 thalassemia variant (HbVar database and references therein). This variant is found in the general population with an overall allele frequency of 0.0004% (1/251288 alleles) in the Genome Aggregation Database. Based on the absence of clinical symptoms associated with the variant, Hb Riyadh is considered to be benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html -

Jun 10, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)). -

not specified

Pathogenic:1

Jan 01, 1979

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.0076

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.079

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.82

.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.34

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over