rs35103459

Positions:

• chr11-5254330-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000184.3(HBG2):​c.277C>T​(p.His93Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBG2 NM_000184.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.51

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a binding_site proximal binding residue (size 0) in uniprot entity HBG2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 11-5254330-G-A is Pathogenic according to our data. Variant chr11-5254330-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14989.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBG2	NM_000184.3	c.277C>T	p.His93Tyr	missense_variant	2/3	ENST00000336906.6	NP_000175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBG2	ENST00000336906.6	c.277C>T	p.His93Tyr	missense_variant	2/3	1	NM_000184.3	ENSP00000338082	P1
HBG2	ENST00000380252.6	c.112C>T	p.His38Tyr	missense_variant	2/3	3		ENSP00000369602
HBG2	ENST00000444587.1	c.*146C>T		3_prime_UTR_variant	2/3	2		ENSP00000488218

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cyanosis, transient neonatal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1989

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 18, 2021

The Hb FM-Fort Ripley variant (HBA1: c.277C>T; p.His93Tyr, also known as His92Tyr when numbered from the mature protein, rs35103459) is reported in the literature in multiple individuals and segregates with disease in large families affected with transient neonatal cyanosis (see link to HbVar, Hain 1994, Hooven 2016, Priest 1989). This variant is also reported in ClinVar (Variation ID: 14989), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 93 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.893). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for Hb FM-Fort Ripley: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=609 Hain RD et al. Hb FM-Fort Ripley: confirmation of autosomal dominant inheritance and diagnosis by PCR and direct nucleotide sequencing. Hum Mutat. 1994;3(3):239-42. PMID: 7517266. Hooven TA et al. Diagnosis of a rare fetal haemoglobinopathy in the age of next-generation sequencing. BMJ Case Rep. 2016 Apr 19;2016:10.1136/bcr-2016-215193. PMID: 27095814. Priest JR et al. Mutant fetal hemoglobin causing cyanosis in a newborn. Pediatrics. 1989 May;83(5):734-6. PMID: 2470017. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;.;H;.
MutationTaster	Benign	1.0	A;A;A
PROVEAN	Pathogenic	-5.6	.;.;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Pathogenic	0.0	.;.;D;.
Polyphen		1.0	.;.;D;.
Vest4		0.94
MutPred		0.98		Loss of methylation at K96 (P = 0.0606);Loss of methylation at K96 (P = 0.0606);Loss of methylation at K96 (P = 0.0606);.;
MVP		0.98
ClinPred		1.0	D
GERP RS		2.0
Varity_R		0.86
gMVP		0.99

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: rs35103459; hg19: chr11-5275560;