chr11-5249456-G-A

Variant names:

• chr11-5249456-G-A
• rs1061234
• NM_000559.3:c.227C>T

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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
• Publications: 25 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: Benign. The variant received -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3	c.227C>T	p.Thr76Ile	missense_variant	Exon 2 of 3	ENST00000330597.5	NP_000550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5	c.227C>T	p.Thr76Ile	missense_variant	Exon 2 of 3	1	NM_000559.3	ENSP00000327431.4
ENSG00000284931	ENST00000642908.1	c.316-969C>T		intron_variant	Intron 2 of 2			ENSP00000495346.1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 38672 AN: 67888 Hom.: 14771 Cov.: 9

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

GnomAD2 exomes AF: 0.357 AC: 44146 AN: 123722 AF XY: 0.338

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 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

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

African (AFR) AF: 0.693 AC: 11314 AN: 16326

American (AMR) AF: 0.565 AC: 14691 AN: 26000

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 9248 AN: 15154

East Asian (EAS) AF: 0.820 AC: 21981 AN: 26798

South Asian (SAS) AF: 0.498 AC: 24593 AN: 49346

European-Finnish (FIN) AF: 0.375 AC: 12582 AN: 33530

Middle Eastern (MID) AF: 0.525 AC: 1345 AN: 2562

European-Non Finnish (NFE) AF: 0.256 AC: 131134 AN: 511752

Other (OTH) AF: 0.465 AC: 14787 AN: 31776

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

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

African (AFR) AF: 0.724 AC: 13157 AN: 18162

American (AMR) AF: 0.639 AC: 3987 AN: 6242

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 1179 AN: 1752

East Asian (EAS) AF: 0.819 AC: 2048 AN: 2500

South Asian (SAS) AF: 0.519 AC: 886 AN: 1706

European-Finnish (FIN) AF: 0.391 AC: 2239 AN: 5724

Middle Eastern (MID) AF: 0.704 AC: 131 AN: 186

European-Non Finnish (NFE) AF: 0.473 AC: 14377 AN: 30384

Other (OTH) AF: 0.598 AC: 495 AN: 828

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary persistence of fetal hemoglobin Benign:1

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HBG1 POLYMORPHISM Benign:1

Jan 01, 1985

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HEMOGLOBIN F (SARDINIA) Other:1

Mar 25, 2021

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		4.5
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
PromoterAI		0.0043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.36
Mutation Taster		=87/13	polymorphism (auto)

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