NM_000518.5:c.180G>C

Variant names:

• chr11-5226712-C-G
• rs34621955
• NM_000518.5:c.180G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000518.5(HBB):​c.180G>C​(p.Lys60Asn) 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 pathogenic outcome for this variant. 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. K60E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: -0.258

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226712-CTT-CA is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.180G>C	p.Lys60Asn	missense_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.180G>C	p.Lys60Asn	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Sep 13, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.180G>C; Lys59Asn variant (rs34621955), also known as Hb J-Lome, is reported in the literature in the heterozygous state in individuals with no clinical symptoms (see link to HbVar and references therein). This variant is reported in ClinVar (Variation ID: 15224), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The lysine at codon 59 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the Hb J-Lome variant is uncertain at this time. References: Link to HbVar for Hb J-Lome: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1185&.cgifields=histD -

beta Thalassemia Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 13, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HEMOGLOBIN J (LOME) Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T;T;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	.;T;T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D;.;.;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.012	D;.;.;D
Sift4G	Benign	0.11	T;.;.;.
Polyphen		0.77	P;P;.;.
Vest4		0.85
MutPred		0.71		Loss of methylation at K60 (P = 0.0119);Loss of methylation at K60 (P = 0.0119);Loss of methylation at K60 (P = 0.0119);Loss of methylation at K60 (P = 0.0119);
MVP		0.95
MPC		0.059
ClinPred		0.88	D
GERP RS		-9.4
Varity_R		0.35
gMVP		0.85

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: rs34621955; hg19: chr11-5247942;