NM_000518.5:c.327C>G

Variant names:

• chr11-5225715-G-C
• rs34933751
• NM_000518.5:c.327C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_000518.5(HBB):​c.327C>G​(p.Asn109Lys) 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N109S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.625

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225716-T-C is described in Lovd as [Pathogenic].
• PP5: Variant 11-5225715-G-C is Pathogenic according to our data. Variant chr11-5225715-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3336287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.327C>G	p.Asn109Lys	missense_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.327C>G	p.Asn109Lys	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:1

May 01, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.327C>G (p.Asn109Lys) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251212 control chromosomes. c.327C>G has been reported in the literature in one individual affected with Beta Thalassemia in the compound heterozygous state (Schnee_1990). Experimental studies show that this variant abolishes the MaeII recognition site and mice homozygous for this variant have hemolytic anemia and erythrocytes with a shortened lifespan (e.g. Schnee_1990, Suzuki_2002, Izumizaki_2003). This variant is also known as Hb Presbyterian. The following publications have been ascertained in the context of this evaluation (PMID: 12829441, 2307460, 12127975).ClinVar contains an entry for this variant (Variation ID: 15318). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Jun 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.327C>G (p.Asn109Lys) variant has been reported in the published literature in individuals with mild anemia (PMIDs: 668922 (1978), 500379 (1979), 3101357 (1986), anemia (PMID: 6309649 (1983)), and hypochromic microcytic anemia (PMID: 28395541 (2017)). Functional studies have demonstrated a decreased oxygen affinity and decreased stability (PMIDs: 12458204 (2003) and 12127975 (2002)). However, heterozygotes may have no hematologic abnormalities (PMID: 12127975 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic. -

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

May 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0090	D;.
Sift4G	Benign	0.094	T;.
Polyphen		0.47	P;P
Vest4		0.45
MutPred		0.77		Gain of methylation at N109 (P = 0.0283);Gain of methylation at N109 (P = 0.0283);
MVP		0.87
MPC		0.073
ClinPred		0.87	D
GERP RS		-3.5
Varity_R		0.48
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34933751; hg19: chr11-5246945;