rs34438981

Variant names:

• chr11-5254683-A-G
• rs34438981
• NM_000184.3:c.46T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000184.3(HBG2):​c.46T>C​(p.Trp16Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 5.03
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG2	NM_000184.3	c.46T>C	p.Trp16Arg	missense_variant	Exon 1 of 3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.46T>C	p.Trp16Arg	missense_variant	Exon 1 of 3	1	NM_000184.3	ENSP00000338082.4
ENSG00000284931	ENST00000642908.1	c.46T>C	p.Trp16Arg	missense_variant	Exon 1 of 3			ENSP00000495346.1
ENSG00000239920	ENST00000380259.7	n.*1349T>C		non_coding_transcript_exon_variant	Exon 7 of 8	5		ENSP00000369609.3
ENSG00000239920	ENST00000380259.7	n.*1349T>C		3_prime_UTR_variant	Exon 7 of 8	5		ENSP00000369609.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 9

GnomAD4 genome Cov.: 23

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN F (CATALONIA) Other:1

Aug 05, 2011

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.28	.;.;T;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D;D;D;.
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.2	.;.;H;.
PhyloP100		5.0
PROVEAN	Pathogenic	-12	.;.;D;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Uncertain	0.021	.;.;D;.
Polyphen		0.87	.;.;P;.
Vest4		0.73, 0.46
MutPred		0.87		Gain of methylation at W16 (P = 0.0124);Gain of methylation at W16 (P = 0.0124);Gain of methylation at W16 (P = 0.0124);Gain of methylation at W16 (P = 0.0124);
MVP		0.97
ClinPred		0.98	D
GERP RS		1.3
PromoterAI		0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.81
gMVP		0.90
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34438981; hg19: chr11-5275913;