chr11-5248418-C-A

Position:

• chr11-5248418-C-A

Variant summary

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

The NM_000559.3(HBG1):​c.385G>T​(p.Ala129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A129T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: Not reported in ClinVar
• 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	Protein	UniProt
HBG1	NM_000559.3	c.385G>T	p.Ala129Ser	missense_variant	3/3	ENST00000330597.5	NP_000550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5	c.385G>T	p.Ala129Ser	missense_variant	3/3	1	NM_000559.3	ENSP00000327431	P1
HBG1	ENST00000648735.1	n.1316G>T		non_coding_transcript_exon_variant	2/2
HBG1	ENST00000632727.1			downstream_gene_variant		3		ENSP00000488759

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.85	D;D;T
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Uncertain	0.25	D
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0080	D;.;.
Sift4G	Uncertain	0.025	D;.;.
Polyphen		0.35	B;.;.
Vest4		0.15
MutPred		0.67		Gain of disorder (P = 0.0157);Gain of disorder (P = 0.0157);.;
MVP		0.95
MPC		1.3
ClinPred		0.99	D
GERP RS		0.61
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.0
gMVP		0.49

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;