11-5225638-A-G

Position:

chr11-5225638-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP5

The NM_000518.5(HBB):c.404T>C(p.Val135Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V135E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3O:1

Conservation

PhyloP100: 2.42

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5225638-A-T is described in Lovd as [Pathogenic].

PP5

Variant 11-5225638-A-G is Pathogenic according to our data. Variant chr11-5225638-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15588.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.404T>C	p.Val135Ala	missense_variant	3/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBB	ENST00000335295.4 linkuse as main transcript	c.404T>C	p.Val135Ala	missense_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1 linkuse as main transcript	c.404T>C	p.Val135Ala	missense_variant	3/3			ENSP00000494175	P1
HBB	ENST00000633227.1 linkuse as main transcript	c.*220T>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000488004
HBB	ENST00000475226.1 linkuse as main transcript			downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251372

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000578

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000169

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000267

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 12, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 23, 2023

Variant summary: HBB c.404T>C (p.Val135Ala), also known as Hb Mataro and Hb Yaounde, results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The sidechain of residue 135 is oriented to the inside of the molecule, and looking toward other hydrophobic residues, therefore replacement of valine by alanine (both having aliphatic side chains of similar size) does not seem to grossly alter the geometry of this region (Arends 1977, Faustino 2004). The variant allele was found at a frequency of 3.2e-05 in 251372 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, p.Val135Ala, has been reported in the literature in multiple asymptomatic individuals. Faustino_2004 reported a family that carried the variant in trans with HbC (p.Glu7Lys), and concluded that the variant does not cause clinical or hematological manifestations. Yapo_2001 also referred to the variant as neutral, with no hematological consequence, after reporting it in an individual who was compound heterozygous for the variant and Hb Kenitra (p.Gly70Arg). Vinciguerra_2015 reported two family members as compound heterozygotes for this variant and the anti 3.7 alpha-globin gene triplication with no symptoms, and hematological parameters comparable to individuals carrying only the other variant. These co-occurrences with other pathogenic (or potentially pathogenic) hemoglobin variants in asymptomatic individuals provide supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 891976, 33851260, 15481891, 19429541, 21353607, 26635043, 17932132, 11523095, 31553106, 25113778, 19500561, 11300355, 15065210). Two ClinVar submitters (evaluation after 2014) cites the variant as uncertain significance, while another ClinVar submitter (evaluation after 2014) cites it as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional evidence of clinical and or functional importance becomes available. -

beta Thalassemia

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 11, 2018

- -

HEMOGLOBIN YAOUNDE

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

0.35

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

.;T

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

0.52

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

N;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.010

D;.

Sift4G

Uncertain

0.041

D;.

Polyphen

0.069

B;B

Vest4

0.79

MVP

0.67

MPC

0.048

ClinPred

0.21

GERP RS

1.1

Varity_R

0.37

gMVP

0.94

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