rs34501593

Positions:

• chr11-5254707-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000184.3(HBG2):​c.22G>A​(p.Asp8Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.607

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBG2	NM_000184.3	c.22G>A	p.Asp8Asn	missense_variant	1/3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.22G>A	p.Asp8Asn	missense_variant	1/3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.22G>A	p.Asp8Asn	missense_variant	1/3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	n.*1325G>A		non_coding_transcript_exon_variant	7/8	5		ENSP00000369609.3
ENSG00000239920	ENST00000380259.7	n.*1325G>A		3_prime_UTR_variant	7/8	5		ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 579476 Hom.: 0 Cov.: 7 AF XY: 0.00 AC XY: 0 AN XY: 304682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN F (AUCKLAND) Other:1

other, no assertion criteria provided

literature only

OMIM

Aug 05, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	.;.;T;.
Eigen	Benign	0.00088
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T;T;T;.
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.1	.;.;M;.
PROVEAN	Benign	-1.7	.;.;N;.
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.0060	.;.;D;.
Polyphen		0.25	.;.;B;.
Vest4		0.22, 0.16
MutPred		0.56		Loss of ubiquitination at K9 (P = 0.1372);Loss of ubiquitination at K9 (P = 0.1372);Loss of ubiquitination at K9 (P = 0.1372);Loss of ubiquitination at K9 (P = 0.1372);
MVP		0.96
ClinPred		0.96	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.62

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: rs34501593; hg19: chr11-5275937;