11-5248048-T-C

Variant names:

• chr11-5248048-T-C
• rs916112
• NM_000559.3:c.*311A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000559.3(HBG1):​c.*311A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 228,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: HBG1 NM_000559.3 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.59
• Publications: 0 publications found

Genes affected

HBG1 (HGNC:4831): (hemoglobin subunit gamma 1) The gamma globin genes (HBG1 and HBG2) are normally expressed in the fetal liver, spleen and bone marrow. Two gamma chains together with two alpha chains constitute fetal hemoglobin (HbF) which is normally replaced by adult hemoglobin (HbA) at birth. In some beta-thalassemias and related conditions, gamma chain production continues into adulthood. The two types of gamma chains differ at residue 136 where glycine is found in the G-gamma product (HBG2) and alanine is found in the A-gamma product (HBG1). The former is predominant at birth. 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]

HBG1 Gene-Disease associations (from GenCC):

• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284931 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000559.3. 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
	HBG1	NM_000559.3	MANE Select	c.*311A>G		downstream_gene	N/A	NP_000550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.*311A>G		downstream_gene	N/A	ENSP00000327431.4	P69891
	ENSG00000284931	ENST00000642908.1		c.*311A>G		downstream_gene	N/A	ENSP00000495346.1	A0AA75LVZ2
	ENSG00000284931	ENST00000647543.1		c.*311A>G		downstream_gene	N/A	ENSP00000496470.1	A0A2R8Y7X9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000438 AC: 1 AN: 228114 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124790

African (AFR) AF: 0.00 AC: 0 AN: 6408

American (AMR) AF: 0.00 AC: 0 AN: 11650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5778

East Asian (EAS) AF: 0.00 AC: 0 AN: 10614

South Asian (SAS) AF: 0.00 AC: 0 AN: 38936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 830

European-Non Finnish (NFE) AF: 0.00000756 AC: 1 AN: 132276

Other (OTH) AF: 0.00 AC: 0 AN: 11760

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.32
DANN	Benign	0.35
PhyloP100		-2.6

Splicing

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

Other links and lift over

dbSNP: rs916112; hg19: chr11-5269278;