chr11-5254380-A-G

Variant names:

• chr11-5254380-A-G
• rs104894225
• NM_000184.3:c.227T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000184.3(HBG2):​c.227T>C​(p.Ile76Thr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I76V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: other no assertion criteria provided O:2
• Conservation: PhyloP100: 4.54

Genes affected

HBG2 (HGNC:4832): (hemoglobin subunit gamma 2) 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]

ENSG00000284931 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.227T>C	p.Ile76Thr	missense_variant	Exon 2 of 3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.227T>C	p.Ile76Thr	missense_variant	Exon 2 of 3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.227T>C	p.Ile76Thr	missense_variant	Exon 2 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	n.*1530T>C		downstream_gene_variant		5		ENSP00000369609.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 17 AN: 152256 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000958 AC: 14 AN: 1461548 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000112 AC: 17 AN: 152256 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74384

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000867

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000237 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: other

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN F (WAYNESBORO) Other:1

Aug 05, 2011

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN F (LESVOS) Other:1

Aug 05, 2011

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	.;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.0	.;.;M;.
PROVEAN	Uncertain	-3.4	.;.;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0090	.;.;D;.
Sift4G	Uncertain	0.037	.;.;D;.
Polyphen		0.35	.;.;B;.
Vest4		0.37
MutPred		0.81		Gain of disorder (P = 0.0095);Gain of disorder (P = 0.0095);Gain of disorder (P = 0.0095);.;
MVP		0.95
ClinPred		0.82	D
GERP RS		2.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.37
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894225; hg19: chr11-5275610;