Variant 11-5225663-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_000518.5(HBB):c.379G>C(p.Val127Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V127A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 0.0600

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5225662-A-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.11904815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.379G>C	p.Val127Leu	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.379G>C	p.Val127Leu	missense_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1 linkuse as main transcript	c.379G>C	p.Val127Leu	missense_variant	3/3			ENSP00000494175	P1
HBB	ENST00000475226.1 linkuse as main transcript	n.311G>C		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1 linkuse as main transcript	c.*195G>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000488004

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727200

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN MOLFETTA

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

0.11

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Benign

7.7

DANN

Benign

0.89

DEOGEN2

Benign

0.013

T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.73

.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.79

N;.

REVEL

Uncertain

0.41

Sift

Benign

0.12

T;.

Sift4G

Benign

0.26

T;.

Polyphen

0.0

B;B

Vest4

0.19

MutPred

0.27

Gain of glycosylation at P126 (P = 0.0972);Gain of glycosylation at P126 (P = 0.0972);

MVP

0.51

MPC

0.033

ClinPred

0.050

GERP RS

-2.2

Varity_R

0.17

gMVP

0.92

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