NM_000559.3:c.110C>G

Variant names:

• chr11-5249573-G-C
• rs41404150
• NM_000559.3:c.110C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000559.3(HBG1):​c.110C>G​(p.Pro37Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 6)
  • Exomes 𝑓: 0.0000025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 7.48
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	NM_000559.3	MANE Select	c.110C>G	p.Pro37Arg	missense	Exon 2 of 3	NP_000550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.110C>G	p.Pro37Arg	missense	Exon 2 of 3	ENSP00000327431.4	P69891
	ENSG00000284931	ENST00000642908.1		c.316-1086C>G		intron	N/A	ENSP00000495346.1	A0AA75LVZ2
	HBG1	ENST00000632727.1	TSL:3	c.72C>G	p.Pro24Pro	synonymous	Exon 2 of 3	ENSP00000488759.1	A0A0J9YYA3

Frequencies

GnomAD3 genomes Cov.: 6

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000253 AC: 2 AN: 791328 Hom.: 0 Cov.: 11 AF XY: 0.00000248 AC XY: 1 AN XY: 403088

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000560 AC: 1 AN: 17850

American (AMR) AF: 0.00 AC: 0 AN: 32684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18932

East Asian (EAS) AF: 0.00 AC: 0 AN: 31196

South Asian (SAS) AF: 0.00 AC: 0 AN: 58942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2860

European-Non Finnish (NFE) AF: 0.00000181 AC: 1 AN: 553182

Other (OTH) AF: 0.00 AC: 0 AN: 36144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 6

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	HEMOGLOBIN F (PENDERGRASS) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.80		Gain of MoRF binding (P = 5e-04)
MVP		0.97
MPC		2.5
ClinPred		0.99	D
GERP RS		2.8
PromoterAI		0.023	Neutral
gMVP		0.78
Mutation Taster		=17/83	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: rs41404150; hg19: chr11-5270803;