rs63750605

Variant names:

• chr11-5227008-G-A
• NM_000518.5:c.14C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-5227008-G-A
• chr11-5227008-G-C
• chr11-5227008-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000518.5(HBB):​c.14C>T​(p.Thr5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,594 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T5N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.179

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 11 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.14C>T	p.Thr5Ile	missense_variant	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.14C>T	p.Thr5Ile	missense_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457594 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725390

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: 9.02e-7

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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	8.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.88	.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.033	D
MutationAssessor	Pathogenic	4.0	H;H;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.4	D;.;.;D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.025	D;.;.;.
Polyphen		0.46	P;P;.;.
Vest4		0.50
MutPred		0.50		Loss of glycosylation at T5 (P = 0.0479);Loss of glycosylation at T5 (P = 0.0479);Loss of glycosylation at T5 (P = 0.0479);Loss of glycosylation at T5 (P = 0.0479);
MVP		0.75
MPC		0.070
ClinPred		0.93	D
GERP RS		-1.7
Varity_R		0.83
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-5248238;