rs35669628

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The ENST00000335295.4(HBB):c.407C>T(p.Ala136Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A136D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HBB
ENST00000335295.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.18

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.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in ENST00000335295.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5225635-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.37200397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.407C>T	p.Ala136Val	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.407C>T	p.Ala136Val	missense_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1 linkuse as main transcript	c.407C>T	p.Ala136Val	missense_variant	3/3			ENSP00000494175	P1
HBB	ENST00000633227.1 linkuse as main transcript	c.*223C>T		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

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251362

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135860

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:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727204

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

Nov 01, 2023

Variant summary: HBB c.407C>T (p.Ala136Val) 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 variant allele was found at a frequency of 1.6e-05 in 251362 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.407C>T has been reported in the literature in at least one compound heterozygous individual affected with Hemoglobinopathy (e.g., Godbole_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a mildly decreased oxygen affinity (e.g., Zubriggen_2009). The following publications have been ascertained in the context of this evaluation (PMID: 29651865, 29365076, 19958196). No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Additionally, other missense variants have been reported in the literature in individuals affected with hemolytic anemia (c.406G>C (p.Ala136Pro) also known as Hb Altdorf) or silent hemoglobinopathies (c.407C>A (p.Ala136Asp), also known as Hb Beckman), and these other missense variants were found to be unstable and result in changes in oxygen affinity (PMIDs: 8450301, 1261680, 19453576, 26209877; Yucel_2013, no PMID)). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.037

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.72

.;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.37

T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

3.4

M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.7

N;.

REVEL

Uncertain

0.56

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.057

T;.

Polyphen

0.090

B;B

Vest4

0.40

MutPred

0.38

Loss of disorder (P = 0.1535);Loss of disorder (P = 0.1535);

MVP

0.75

MPC

0.034

ClinPred

0.77

GERP RS

3.8

Varity_R

0.23

gMVP

0.81

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