Genetic Variant ENST00000485743.1:c.316G>C (chr11-5226576-C-G) – ACMG Classification: Pathogenic (24 pts)

Variant summary

Our verdict is . The variant received 24 ACMG points: 24P and 0B. PS1_Very_StrongPS3PM1PM2PM5PP3_StrongPP5_Moderate

The ENST00000485743.1(HBB):c.316G>C(p.Val106Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002246990: RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein.". Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V106G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HBB
ENST00000485743.1 missense

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 5.66

Publications

52 publications found

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 Gene-Disease associations (from GenCC):

dominant beta-thalassemia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
erythrocytosis, familial, 6
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
hemoglobin M disease
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, PanelApp Australia
unstable hemoglobin disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
beta thalassemia
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women's Health
sickle cell disease and related diseases
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
beta-thalassemia HBB/LCRB
Inheritance: SD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
Heinz body anemia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
hereditary persistence of fetal hemoglobin
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
delta-beta-thalassemia
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
sickle cell disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
beta-thalassemia intermedia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
beta-thalassemia major
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin C disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin C-beta-thalassemia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin E disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin E-beta-thalassemia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-beta-thalassemia disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin c disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin d disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
sickle cell-hemoglobin E disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HBB links:

ENSG00000298932 (HGNC:):

ENSG00000298932 links:

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new If you want to explore the variant's impact on the transcript ENST00000485743.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 24 ACMG points.

PS1

Transcript ENST00000485743.1 (HBB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002246990: RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein.

PM1

In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 21 uncertain in ENST00000485743.1

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226575-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 439146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-5226576-C-G is Pathogenic according to our data. Variant chr11-5226576-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 189128.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000485743.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.315+1G>C		splice_donor intron	N/A	NP_000509.1	D9YZU5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HBB	ENST00000485743.1	TSL:1	c.316G>C	p.Val106Leu	missense	Exon 2 of 2	ENSP00000496200.1	A0A2R8Y7R2
HBB	ENST00000335295.4	TSL:1 MANE Select	c.315+1G>C		splice_donor intron	N/A	ENSP00000333994.3	P68871
HBB	ENST00000647020.1		c.315+1G>C		splice_donor intron	N/A	ENSP00000494175.1	P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461262

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111454

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

beta Thalassemia (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

PhyloP100

5.7

PromoterAI

-0.24

Neutral

(source)

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over