11-5227014-T-C

Position:

• chr11-5227014-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP6

The NM_000518.5(HBB):​c.8A>G​(p.His3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,445,526 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• 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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5227013-A-T is described in Lovd as [Pathogenic].
• BP6: Variant 11-5227014-T-C is Benign according to our data. Variant chr11-5227014-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15156.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.8A>G	p.His3Arg	missense_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.8A>G	p.His3Arg	missense_variant	1/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251140 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135736

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: 0.00000208 AC: 3 AN: 1445526 Hom.: 0 Cov.: 26 AF XY: 0.00000278 AC XY: 2 AN XY: 720296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 18, 2023	The HBB c.8A>G (p.His3Arg) variant (also known as Hb Deer Lodge) has been reported to have normal stability with slightly increased oxygen affinity and decreased cooperativity (PMID: 393 (1975)). Individuals who are heterozygous for this variant have a normal clinical presentation (), and PMIDs: 3384712 (1988), 1052174 (1976)). Co-occurrence of this variant with Hb S present with simple sickle cell trait (PMID: 1052174 (1976)). Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2019	- -

HEMOGLOBIN DEER LODGE Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.097	T;T;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	.;T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.7	D;.;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D;.;.;D
Sift4G	Uncertain	0.044	D;.;.;.
Polyphen		0.0030	B;B;.;.
Vest4		0.85
MutPred		0.56		Gain of phosphorylation at T5 (P = 0.1042);Gain of phosphorylation at T5 (P = 0.1042);Gain of phosphorylation at T5 (P = 0.1042);Gain of phosphorylation at T5 (P = 0.1042);
MVP		0.81
MPC		0.038
ClinPred		0.30	T
GERP RS		4.0
Varity_R		0.42
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs33983205; hg19: chr11-5248244;