rs1609812

Variant names:

• chr11-5225911-G-A
• rs1609812
• NM_000518.5:c.316-185C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-5225911-G-A
• chr11-5225911-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000518.5(HBB):​c.316-185C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 152,150 control chromosomes in the GnomAD database, including 51,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.82 (51216 hom., cov: 32)
• Consequence: HBB NM_000518.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.59
• Publications: 38 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• erythrocytosis, familial, 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet
• unstable hemoglobin disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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
• delta-beta-thalassemia

  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

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-5225911-G-A is Benign according to our data. Variant chr11-5225911-G-A is described in ClinVar as Benign. ClinVar VariationId is 36316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000518.5. 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.316-185C>T		intron	N/A	NP_000509.1	D9YZU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	ENST00000335295.4	TSL:1 MANE Select	c.316-185C>T		intron	N/A	ENSP00000333994.3	P68871
	HBB	ENST00000647020.1		c.316-185C>T		intron	N/A	ENSP00000494175.1	P68871
	HBB	ENST00000883533.1		c.316-185C>T		intron	N/A	ENSP00000553592.1

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124056 AN: 152032 Hom.: 51185 Cov.: 32

Gnomad AFR AF: 0.869

Gnomad AMI AF: 0.971

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.823

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

GnomAD4 genome AF: 0.816 AC: 124145 AN: 152150 Hom.: 51216 Cov.: 32 AF XY: 0.807 AC XY: 60043 AN XY: 74374

African (AFR) AF: 0.869 AC: 36085 AN: 41512

American (AMR) AF: 0.727 AC: 11110 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 2999 AN: 3472

East Asian (EAS) AF: 0.495 AC: 2558 AN: 5172

South Asian (SAS) AF: 0.625 AC: 3010 AN: 4816

European-Finnish (FIN) AF: 0.787 AC: 8330 AN: 10578

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.841 AC: 57185 AN: 68000

Other (OTH) AF: 0.819 AC: 1728 AN: 2110

Alfa AF: 0.829 Hom.: 74893

Bravo AF: 0.820

Asia WGS AF: 0.574 AC: 1998 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	beta Thalassemia (5)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.37
DANN	Benign	0.11
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1609812; hg19: chr11-5247141;