rs33991294

chr11-5226660-G-Achr11-5226660-G-Cchr11-5226660-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP3_Moderate

The NM_000518.5(HBB):c.232C>T(p.His78Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. H78D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 0.993

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 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_000518.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226660-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.232C>T	p.His78Tyr	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.232C>T	p.His78Tyr	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251428 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135878

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

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

Jul 25, 2022

Variant summary: HBB c.232C>T (p.His78Tyr) also known as Hb-Fukuyama results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251428 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.232C>T has been reported in the literature as a slightly unstable hemoglobin in reportedly unaffected individuals during routine HbA1c analysis (example, Landin_1993). These report(s) do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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.

Jul 08, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 25, 2019

The Hb Fukuyama variant (HBB: c.232C>T; p.His78Tyr, also known as His77Tyr when numbered from the mature protein, rs33991294) is reported in the literature in several heterozygous individuals without clinical symptoms (HbVar database and references therein). This variant is found on a single chromosome (1/251428 alleles) in the Genome Aggregation Database. The histidine at codon 78 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and functional assays suggest the variant is mildly unstable (HbVar database and references therein). However, due to limited information, the clinical significance of the Hb Fukuyama variant is uncertain at this time. References: HbVar link to Hb Fukuyama: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=394 -

HEMOGLOBIN FUKUYAMA 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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.073	T;T;.;T
Eigen	Benign	0.038
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.57	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.1	M;M;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.1	D;.;.;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.019	D;.;.;.
Polyphen		0.99	D;D;.;.
Vest4		0.83
MutPred		0.73		Gain of ubiquitination at K83 (P = 0.0762);Gain of ubiquitination at K83 (P = 0.0762);Gain of ubiquitination at K83 (P = 0.0762);Gain of ubiquitination at K83 (P = 0.0762);
MVP		0.93
MPC		0.21
ClinPred		0.97	D
GERP RS		1.9
Varity_R		0.67
gMVP		0.67

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: rs33991294; hg19: chr11-5247890; COSMIC: COSV104647177; COSMIC: COSV104647177;