11-5249456-G-A

Position:

• chr11-5249456-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000559.3(HBG1):​c.227C>T​(p.Thr76Ile) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (14806 hom., cov: 9)
  • Exomes 𝑓: 0.34 (115673 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 4.53

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049443543).
• BP6: Variant 11-5249456-G-A is Benign according to our data. Variant chr11-5249456-G-A is described in ClinVar as [Benign]. Clinvar id is 15005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5249456-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBG1	NM_000559.3	c.227C>T	p.Thr76Ile	missense_variant	2/3	ENST00000330597.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBG1	ENST00000330597.5	c.227C>T	p.Thr76Ile	missense_variant	2/3	1	NM_000559.3	P1
HBG1	ENST00000632727.1	c.*96C>T		3_prime_UTR_variant	2/3	3
HBG1	ENST00000648735.1	n.278C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 38672 AN: 67888 Hom.: 14771 Cov.: 9 FAILED QC

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.720

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.591

GnomAD3 exomes AF: 0.357 AC: 44146 AN: 123722 Hom.: 21892 AF XY: 0.338 AC XY: 22220 AN XY: 65650

Gnomad AFR exome AF: 0.702

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.731

Gnomad SAS exome AF: 0.333

Gnomad FIN exome AF: 0.0679

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.410

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.339 AC: 241675 AN: 713244 Hom.: 115673 Cov.: 14 AF XY: 0.351 AC XY: 126461 AN XY: 360300

Gnomad4 AFR exome AF: 0.693

Gnomad4 AMR exome AF: 0.565

Gnomad4 ASJ exome AF: 0.610

Gnomad4 EAS exome AF: 0.820

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.465

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.570 AC: 38747 AN: 67956 Hom.: 14806 Cov.: 9 AF XY: 0.556 AC XY: 18022 AN XY: 32404

Gnomad4 AFR AF: 0.724

Gnomad4 AMR AF: 0.639

Gnomad4 ASJ AF: 0.673

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.519

Gnomad4 FIN AF: 0.391

Gnomad4 NFE AF: 0.473

Gnomad4 OTH AF: 0.598

Alfa AF: 0.648 Hom.: 2145

ExAC AF: 0.290 AC: 20785

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary persistence of fetal hemoglobin Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 20, 2022

- -

HBG1 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 1985

- -

HEMOGLOBIN F (SARDINIA) Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.5
DANN	Benign	0.59
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	3.2	N
REVEL	Benign	0.23
Sift	Benign	0.61	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.050
MPC		1.3
ClinPred		0.0043	T
GERP RS		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.36

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: rs1061234; hg19: chr11-5270686; COSMIC: COSV57963013; COSMIC: COSV57963013;