11-5254691-G-T

Variant names:

• chr11-5254691-G-T
• rs281864890
• NM_000184.3:c.38C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000184.3(HBG2):​c.38C>A​(p.Thr13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T13R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373
• Publications: 1 publications found

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]

HBG2 Gene-Disease associations (from GenCC):

• hemoglobinopathy Toms River

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• cyanosis, transient neonatal

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000284931 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity HBG2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19414067).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000184.3. 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
	HBG2	NM_000184.3	MANE Select	c.38C>A	p.Thr13Lys	missense	Exon 1 of 3	NP_000175.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG2	ENST00000336906.6	TSL:1 MANE Select	c.38C>A	p.Thr13Lys	missense	Exon 1 of 3	ENSP00000338082.4
	ENSG00000284931	ENST00000642908.1		c.38C>A	p.Thr13Lys	missense	Exon 1 of 3	ENSP00000495346.1
	ENSG00000239920	ENST00000380259.7	TSL:5	n.*1341C>A		non_coding_transcript_exon	Exon 7 of 8	ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000314 AC: 2 AN: 636334 Hom.: 0 Cov.: 8 AF XY: 0.00000601 AC XY: 2 AN XY: 332698

⚠️ 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: 17238

American (AMR) AF: 0.00 AC: 0 AN: 29642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17204

East Asian (EAS) AF: 0.00 AC: 0 AN: 32570

South Asian (SAS) AF: 0.0000177 AC: 1 AN: 56540

European-Finnish (FIN) AF: 0.0000279 AC: 1 AN: 35806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2450

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 412458

Other (OTH) AF: 0.00 AC: 0 AN: 32426

⚠️ 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 Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.37
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.70	T
Polyphen		0.24	B
Vest4		0.18
MutPred		0.52		Gain of ubiquitination at T13 (P = 0.0311)
MVP		0.79
ClinPred		0.41	T
GERP RS		1.7
PromoterAI		0.011	Neutral
Varity_R		0.63
gMVP		0.23
Mutation Taster		=20/80	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: rs281864890; hg19: chr11-5275921;