rs33929415

chr11-5225612-G-Achr11-5225612-G-Cchr11-5225612-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 6P and 8B. PM1PM2PM5BP6_Very_Strong

The NM_000518.5(HBB):c.430C>T(p.His144Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H144?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.19

Variant links:

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]

HBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 chr11-5225611-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP6

Variant 11-5225612-G-A is Benign according to our data. Variant chr11-5225612-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 15565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.430C>T	p.His144Tyr	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBB	ENST00000335295.4 linkuse as main transcript	c.430C>T	p.His144Tyr	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1 linkuse as main transcript	c.430C>T	p.His144Tyr	missense_variant	3/3			P1
HBB	ENST00000633227.1 linkuse as main transcript	c.*246C>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	3
HBB	ENST00000475226.1 linkuse as main transcript			downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251382

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135864

show subpopulations

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:

0.00000821

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727234

show subpopulations

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:

0.00000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	literature only	OMIM	Dec 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2021	Variant summary: HBB c.430C>T [p.His144Tyr; also known as Hb Old Dominion/Burton-upon-Trent (OD/BuT) and as legacy name p.His143Tyr] results in a conservative amino acid change located in the Globin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.430C>T has been reported in the literature in multiple individuals with diabetes mellitus who were identified as having an abnormal hemoglobin that co-elutes with hemoglobinA1c, but had no other evidence of hemoglobinopathy (e.g. Elder_1998, Gilbert_2000, Plaseska-Karanfilska_2000). These findings indicate that the variant is unlikely to be associated with hemoglobin-related disease. The only potential clinical consequence that has been observed for this variant is that it co-elutes with HbAlc on ion exchange chromatography and thereby causes a spurious increase in HbAlc, compromising the utility of this test to monitor the treatment of diabetes mellitus in individuals with the variant. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant had a slight increase in oxygen affinity that did not appear to result in a clinical impact (e.g. Elder_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.098

T;T

Eigen

Benign

0.034

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.86

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

0.84

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.9

D;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0090

D;.

Sift4G

Benign

0.064

T;.

Polyphen

0.0060

B;B

Vest4

0.88

MVP

0.94

MPC

0.038

ClinPred

0.55

GERP RS

4.7

Varity_R

0.48

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over