11-5226578-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000518.5(HBB):c.314G>A(p.Arg105Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105?) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HBB NM_000518.5 missense, splice_region
• Scores: Splicing: ADA: 0.00002135
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.210

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 4 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226577-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2135447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.314G>A	p.Arg105Lys	missense_variant, splice_region_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.314G>A	p.Arg105Lys	missense_variant, splice_region_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461772 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727206

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	7.5
Dann	Benign	0.72
DEOGEN2	Benign	0.027	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.51	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.17	N;N;.
MutationTaster	Benign	0.94	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.42	N;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.39	T;.;.
Sift4G	Benign	1.0	T;.;.
Polyphen		0.0	B;B;.
Vest4		0.53
MutPred		0.56		Gain of methylation at R105 (P = 0.0106);Gain of methylation at R105 (P = 0.0106);Gain of methylation at R105 (P = 0.0106);
MVP		0.82
MPC		0.036
ClinPred		0.028	T
GERP RS		-2.3
Varity_R		0.24
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.012
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: rs33911434; hg19: chr11-5247808; COSMIC: COSV100092722; COSMIC: COSV100092722;