chr11-5226583-G-T

Position:

• chr11-5226583-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000518.5(HBB):​c.309C>A​(p.Asn103Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N103S) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.62

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226583-GTT-GGA is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.309C>A	p.Asn103Lys	missense_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.309C>A	p.Asn103Lys	missense_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 22, 2023

Variant summary: HBB c.309C>A (p.Asn103Lys; a.k.a. Hb Richmond) results in a non-conservative amino acid change located in the Globin of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251380 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.309C>A, has been identified in compound heterozygosity with HbS and HbC variants without in vivo sickling and hemolysis. Mild microcytic anemia and polycythemia caused by elevated oxygen affinity, often silent, was also reported. Oxygen affinity studies showed normal readings in the whole blood but slightly higher affinity for oxygen of purified Hb Richmond (Efremov_1969). The variant of interest may be a benign structural variant, however since no reports of homozygosity or compound heterozygosity with B-thal-0 were published at the time of scoring, the clinical significant of Hb Richmond cannot be assessed with confidence. The following publications have been ascertained in the context of this evaluation (PMID: 27207683, 4981790, 26635043, 6859036, 19429541, 19750260, 29365076, 239952, 24200101). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

beta Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 11, 2023

The HBB c.309C>A (p.Asn103Lys) variant (also known as Hb Richmond or CD 102 AAC>AAA or AAG) has been reported in the published literature in heterozygotes with a normal clinical presentation in the published literature (PMID: 4981790 (1969), and 6859036 (1983)). Functional studies suggest this variant may not be damaging to normal function but are inconclusive (PMID: 4981790 (1969), 5283757 (1971), and 239952 (1975)). The frequency of this variant in the general population, 0.0000066 (1/152160 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.6	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.1	D;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0070	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.92		Gain of methylation at N103 (P = 0.0052);Gain of methylation at N103 (P = 0.0052);Gain of methylation at N103 (P = 0.0052);
MVP		0.97
MPC		0.24
ClinPred		0.99	D
GERP RS		-0.0080
Varity_R		0.84
gMVP		0.96

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: rs34227486; hg19: chr11-5247813;