dbSNP rs558554234: HBB:c.316-238C>T (chr11-5225964-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_000518.5(HBB):c.316-238C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 152,242 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 2 hom., cov: 32)

Consequence

HBB
NM_000518.5 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1B:4

Conservation

PhyloP100: -0.598

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-5225964-G-A is Benign according to our data. Variant chr11-5225964-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225964-G-A is described in Lovd as [Benign]. Variant chr11-5225964-G-A is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAd4 at 2 SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.316-238C>T		intron_variant	Intron 2 of 2	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBB	ENST00000335295.4 link	c.316-238C>T	intron_variant	Intron 2 of 2	1	NM_000518.5	ENSP00000333994.3	P68871
HBB	ENST00000647020.1 link	c.316-238C>T	intron_variant	Intron 2 of 2			ENSP00000494175.1	P68871
HBB	ENST00000475226.1 link	n.248-238C>T	intron_variant	Intron 1 of 1	2
HBB	ENST00000633227.1 link	n.*132-238C>T	intron_variant	Intron 2 of 2	3		ENSP00000488004.1	A0A0J9YWK4

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.000525

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.000117

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.316-238C>T is located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing (TRaP). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00053 in 152242 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia (0.00053 vs 0.011), allowing no conclusion about variant significance. c.316-238C>T has been reported in the literature in individuals affected with Beta Thalassemia (Sjahi_2003, Edison_2008, Nadkarni_2009, Colah_2009, Ozlap_2024). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12709369, 21119755, 18294253, 19254853, 19205975, 38708170). ClinVar contains an entry for this variant (Variation ID: 256347). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:2

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

beta Thalassemia

Pathogenic:1

Mar 08, 2018

Hb Lab, Kinderklinik Ulm, University Hospital Ulm

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Rare thalassemic variant that could cause severe Thalassemia (Major or intermedia) when associated with other more common beta0 thalassemic alleles. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.52

DANN

Benign

0.30

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