rs34427034

Variant names:

• chr11-5249789-C-T
• rs34427034
• NM_000559.3:c.16G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_000559.3(HBG1):​c.16G>A​(p.Glu6Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 5)
  • Exomes 𝑓: 0.0000033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 2.02
• Publications: 3 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08145425).
• BP6: Variant 11-5249789-C-T is Benign according to our data. Variant chr11-5249789-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 15024.Status of the report is criteria_provided_single_submitter, 1 stars.

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.16G>A	p.Glu6Lys	missense	Exon 1 of 3	NP_000550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.16G>A	p.Glu6Lys	missense	Exon 1 of 3	ENSP00000327431.4	P69891
	ENSG00000284931	ENST00000642908.1		c.316-1302G>A		intron	N/A	ENSP00000495346.1	A0AA75LVZ2
	HBG1	ENST00000632727.1	TSL:3	c.16G>A	p.Glu6Lys	missense	Exon 1 of 3	ENSP00000488759.1	A0A0J9YYA3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 28606 Hom.: 0 Cov.: 5

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000332 AC: 1 AN: 301650 Hom.: 0 Cov.: 0 AF XY: 0.00000628 AC XY: 1 AN XY: 159156

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000115 AC: 1 AN: 8664

American (AMR) AF: 0.00 AC: 0 AN: 13886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8922

East Asian (EAS) AF: 0.00 AC: 0 AN: 17944

South Asian (SAS) AF: 0.00 AC: 0 AN: 36226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 178434

Other (OTH) AF: 0.00 AC: 0 AN: 16630

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 28606 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 12742

African (AFR) AF: 0.00 AC: 0 AN: 5112

American (AMR) AF: 0.00 AC: 0 AN: 2210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 740

East Asian (EAS) AF: 0.00 AC: 0 AN: 1048

South Asian (SAS) AF: 0.00 AC: 0 AN: 862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 122

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 15846

Other (OTH) AF: 0.00 AC: 0 AN: 338

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary persistence of fetal hemoglobin (1)
-	-	-	HEMOGLOBIN F (TEXAS I) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.68	T
PhyloP100		2.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.28
Sift	Uncertain	0.012	D
Sift4G	Benign	0.70	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.60		Gain of ubiquitination at E6 (P = 0.0155)
MVP		0.79
MPC		1.3
ClinPred		0.17	T
GERP RS		-1.1
PromoterAI		0.021	Neutral
gMVP		0.33
Mutation Taster		=40/60	disease causing

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: rs34427034; hg19: chr11-5271019;