ENST00000644706.1:n.180A>C

Variant names:

• chr11-5225282-T-G
• rs7110263
• ENST00000644706.1:n.180A>C

Variant summary

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

The ENST00000644706.1(ENSG00000285498):​n.180A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 390,910 control chromosomes in the GnomAD database, including 122,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50180 hom., cov: 32)
  • Exomes 𝑓: 0.77 (72554 hom.)
• Consequence: ENSG00000285498 ENST00000644706.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.137
• Publications: 6 publications found

Genes affected

ENSG00000285498 (HGNC:):

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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, 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), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, 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
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-5225282-T-G is Benign according to our data. Variant chr11-5225282-T-G is described in ClinVar as Benign. ClinVar VariationId is 256342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644706.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBB	NM_000518.5	MANE Select	c.*316A>C		downstream_gene	N/A	NP_000509.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285498	ENST00000644706.1		n.180A>C		non_coding_transcript_exon	Exon 1 of 1
	HBB	ENST00000335295.4	TSL:1 MANE Select	c.*316A>C		downstream_gene	N/A	ENSP00000333994.3
	HBB	ENST00000647020.1		c.*316A>C		downstream_gene	N/A	ENSP00000494175.1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122778 AN: 152016 Hom.: 50140 Cov.: 32

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.969

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.848

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.818

GnomAD4 exome AF: 0.772 AC: 184417 AN: 238776 Hom.: 72554 Cov.: 2 AF XY: 0.760 AC XY: 98364 AN XY: 129344

African (AFR) AF: 0.867 AC: 6032 AN: 6956

American (AMR) AF: 0.690 AC: 7996 AN: 11584

Ashkenazi Jewish (ASJ) AF: 0.843 AC: 5336 AN: 6328

East Asian (EAS) AF: 0.498 AC: 5626 AN: 11292

South Asian (SAS) AF: 0.636 AC: 25246 AN: 39724

European-Finnish (FIN) AF: 0.784 AC: 8223 AN: 10486

Middle Eastern (MID) AF: 0.861 AC: 797 AN: 926

European-Non Finnish (NFE) AF: 0.829 AC: 115119 AN: 138874

Other (OTH) AF: 0.797 AC: 10042 AN: 12606

GnomAD4 genome AF: 0.808 AC: 122874 AN: 152134 Hom.: 50180 Cov.: 32 AF XY: 0.799 AC XY: 59451 AN XY: 74366

African (AFR) AF: 0.865 AC: 35926 AN: 41514

American (AMR) AF: 0.722 AC: 11033 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 2940 AN: 3468

East Asian (EAS) AF: 0.494 AC: 2549 AN: 5156

South Asian (SAS) AF: 0.623 AC: 2992 AN: 4802

European-Finnish (FIN) AF: 0.778 AC: 8240 AN: 10596

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56341 AN: 68000

Other (OTH) AF: 0.814 AC: 1716 AN: 2108

Alfa AF: 0.822 Hom.: 69692

Bravo AF: 0.812

Asia WGS AF: 0.570 AC: 1986 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	beta Thalassemia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.51
PhyloP100		-0.14

Splicing

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

Other links and lift over

dbSNP: rs7110263; hg19: chr11-5246512;