rs35315638

Variant names:

• chr11-5249796-A-C
• rs35315638
• NM_000559.3:c.9T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000559.3(HBG1):​c.9T>G​(p.His3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 5)
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.0670
• Publications: 1 publications found

Genes affected

HBG1 (HGNC:4831): (hemoglobin subunit gamma 1) 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]

HBG1 Gene-Disease associations (from GenCC):

• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284931 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2819513).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000559.3. 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
	HBG1	NM_000559.3	MANE Select	c.9T>G	p.His3Gln	missense	Exon 1 of 3	NP_000550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.9T>G	p.His3Gln	missense	Exon 1 of 3	ENSP00000327431.4
	ENSG00000284931	ENST00000642908.1		c.316-1309T>G		intron	N/A	ENSP00000495346.1
	HBG1	ENST00000632727.1	TSL:3	c.9T>G	p.His3Gln	missense	Exon 1 of 3	ENSP00000488759.1

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 5

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN F (MACEDONIA-I) Other:1

Jul 15, 2011

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	7.9
DANN	Benign	0.73
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.29	T
PhyloP100		0.067
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.022	D
Sift4G	Benign	0.090	T
Polyphen		0.015	B
Vest4		0.16
MutPred		0.73		Gain of phosphorylation at T5 (P = 0.3148)
MVP		0.70
MPC		1.3
ClinPred		0.14	T
GERP RS		-4.1
PromoterAI		0.049	Neutral
gMVP		0.12
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35315638; hg19: chr11-5271026;