11-5249390-T-C

Variant names:

• chr11-5249390-T-C
• rs34127117
• NM_000559.3:c.293A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000559.3(HBG1):​c.293A>G​(p.His98Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H98L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000096 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000010 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 1.64
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	NM_000559.3	MANE Select	c.293A>G	p.His98Arg	missense	Exon 2 of 3	NP_000550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.293A>G	p.His98Arg	missense	Exon 2 of 3	ENSP00000327431.4
	ENSG00000284931	ENST00000642908.1		c.316-903A>G		intron	N/A	ENSP00000495346.1
	HBG1	ENST00000648735.1		n.344A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00000961 AC: 1 AN: 104078 Hom.: 0 Cov.: 15

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: 0.0000216

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000871 AC: 2 AN: 229564 AF XY: 0.0000161

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000104 AC: 12 AN: 1156038 Hom.: 2 Cov.: 23 AF XY: 0.0000121 AC XY: 7 AN XY: 580648

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

African (AFR) AF: 0.00 AC: 0 AN: 26646

American (AMR) AF: 0.00 AC: 0 AN: 41722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23152

East Asian (EAS) AF: 0.00 AC: 0 AN: 35894

South Asian (SAS) AF: 0.00 AC: 0 AN: 75794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4688

European-Non Finnish (NFE) AF: 0.0000141 AC: 12 AN: 852440

Other (OTH) AF: 0.00 AC: 0 AN: 48416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00275900), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000961 AC: 1 AN: 104078 Hom.: 0 Cov.: 15 AF XY: 0.0000198 AC XY: 1 AN XY: 50538

African (AFR) AF: 0.00 AC: 0 AN: 28174

American (AMR) AF: 0.00 AC: 0 AN: 10172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2676

East Asian (EAS) AF: 0.00 AC: 0 AN: 3940

South Asian (SAS) AF: 0.00 AC: 0 AN: 2722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.0000216 AC: 1 AN: 46216

Other (OTH) AF: 0.00 AC: 0 AN: 1288

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN F (DICKINSON) Other:1

Jul 15, 2011

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	0.10
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.45	D
PhyloP100		1.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.29	T
Polyphen		0.94	P
Vest4		0.19
MVP		0.95
MPC		2.1
ClinPred		0.99	D
GERP RS		2.2
PromoterAI		0.026	Neutral
gMVP		0.50
Mutation Taster		=56/44	polymorphism

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: rs34127117; hg19: chr11-5270620;