11-5248393-G-C

Variant names:

• chr11-5248393-G-C
• rs56205611
• NM_000559.3:c.410C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000559.3(HBG1):​c.410C>G​(p.Ala137Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 152,242 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A137S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0065 (13 hom., cov: 30)
  • Exomes 𝑓: 0.00086 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.423
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008590221).
• BP6: Variant 11-5248393-G-C is Benign according to our data. Variant chr11-5248393-G-C is described in ClinVar as [Benign]. Clinvar id is 478899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00648 (986/152242) while in subpopulation AFR AF = 0.0214 (890/41520). AF 95% confidence interval is 0.0203. There are 13 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBG1	NM_000559.3	c.410C>G	p.Ala137Gly	missense_variant	Exon 3 of 3	ENST00000330597.5	NP_000550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBG1	ENST00000330597.5	c.410C>G	p.Ala137Gly	missense_variant	Exon 3 of 3	1	NM_000559.3	ENSP00000327431.4
ENSG00000284931	ENST00000642908.1	c.410C>G	p.Ala137Gly	missense_variant	Exon 3 of 3			ENSP00000495346.1

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 982 AN: 152124 Hom.: 13 Cov.: 30

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00457 AC: 1015 AN: 222246 AF XY: 0.00461

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00169

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00434

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000862 AC: 1259 AN: 1461064 Hom.: 5 Cov.: 34 AF XY: 0.000865 AC XY: 629 AN XY: 726848

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

African (AFR) AF: 0.0167 AC: 553 AN: 33198

American (AMR) AF: 0.00227 AC: 101 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39692

South Asian (SAS) AF: 0.00193 AC: 166 AN: 86186

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.000289 AC: 321 AN: 1111756

Other (OTH) AF: 0.00139 AC: 84 AN: 60352

⚠️ 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 AF: 0.00648 AC: 986 AN: 152242 Hom.: 13 Cov.: 30 AF XY: 0.00617 AC XY: 459 AN XY: 74424

African (AFR) AF: 0.0214 AC: 890 AN: 41520

American (AMR) AF: 0.00242 AC: 37 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.0194 Hom.: 0

ExAC AF: 0.0610 AC: 7401

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	5.6
DANN	Benign	0.72
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.39	T;T;T
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		0.42
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.79	N;.;.
REVEL	Benign	0.20
Sift	Benign	1.0	T;.;.
Sift4G	Benign	0.56	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.033
MPC		1.2
ClinPred		0.000022	T
GERP RS		1.7
gMVP		0.32
Mutation Taster		=83/17	polymorphism

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: rs56205611; hg19: chr11-5269623; COSMIC: COSV57963391; COSMIC: COSV57963391;