11-5248418-C-T

Position:

• chr11-5248418-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000559.3(HBG1):​c.385G>A​(p.Ala129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.345

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBG1	NM_000559.3	c.385G>A	p.Ala129Thr	missense_variant	3/3	ENST00000330597.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBG1	ENST00000330597.5	c.385G>A	p.Ala129Thr	missense_variant	3/3	1	NM_000559.3	P1
HBG1	ENST00000648735.1	n.1316G>A		non_coding_transcript_exon_variant	2/2
HBG1	ENST00000632727.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN F (BASKENT) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.88	D;D;T
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.0	D;.;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0090	D;.;.
Sift4G	Uncertain	0.011	D;.;.
Polyphen		0.99	D;.;.
Vest4		0.35
MutPred		0.67		Gain of methylation at K133 (P = 0.0509);Gain of methylation at K133 (P = 0.0509);.;
MVP		0.98
MPC		2.0
ClinPred		0.99	D
GERP RS		0.61
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
gMVP		0.48

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: rs41330850; hg19: chr11-5269648; COSMIC: COSV57964033; COSMIC: COSV57964033;