rs33929459

chr11-5226952-C-Achr11-5226952-C-Gchr11-5226952-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000518.5(HBB):c.70G>T(p.Val24Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V24A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic; other no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.0490

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 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 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 chr11-5226952-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 478897.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 11-5226952-C-A is Pathogenic according to our data. Variant chr11-5226952-C-A is described in ClinVar as [Pathogenic, other]. Clinvar id is 15306.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.70G>T	p.Val24Phe	missense_variant	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.70G>T	p.Val24Phe	missense_variant	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251308 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461576 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727130

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Erythrocytosis, familial, 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1982

- -

HEMOGLOBIN PALMERSTON NORTH 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	0.31
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.038	T;T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.16	N
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Benign	1.7	L;L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.7	D;.;.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.019	D;.;.;D
Sift4G	Benign	0.10	T;.;.;.
Polyphen		0.32	B;B;.;.
Vest4		0.81
MutPred		0.54		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.79
MPC		0.062
ClinPred		0.41	T
GERP RS		-1.3
Varity_R		0.51
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs33929459; hg19: chr11-5248182; COSMIC: COSV58941807; COSMIC: COSV58941807;