chr11-5248400-C-T

Position:

• chr11-5248400-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000559.3(HBG1):​c.403G>A​(p.Val135Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. 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)
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.123

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34275746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBG1	NM_000559.3	c.403G>A	p.Val135Met	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.403G>A	p.Val135Met	missense_variant	3/3	1	NM_000559.3	ENSP00000327431	P1
HBG1	ENST00000648735.1	n.1334G>A		non_coding_transcript_exon_variant	2/2
HBG1	ENST00000632727.1			downstream_gene_variant		3		ENSP00000488759

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HEMOGLOBIN F (JIANGSU) 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	0.28
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	16
DANN	Uncertain	0.98
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Uncertain	0.46	D
MutationTaster	Benign	0.83	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N;.;.
REVEL	Uncertain	0.49
Sift	Benign	0.038	D;.;.
Sift4G	Benign	0.14	T;.;.
Polyphen		0.56	P;.;.
Vest4		0.11
MutPred		0.63		Loss of catalytic residue at V135 (P = 0.0378);Loss of catalytic residue at V135 (P = 0.0378);.;
MVP		0.88
MPC		1.3
ClinPred		0.18	T
GERP RS		2.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.4
gMVP		0.46

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: rs35849660; hg19: chr11-5269630; COSMIC: COSV57963795; COSMIC: COSV57963795;