chr11-5248393-G-C

Position:

• chr11-5248393-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/18 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

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 -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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 986 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBG1	NM_000559.3	c.410C>G	p.Ala137Gly	missense_variant	3/3	ENST00000330597.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBG1	ENST00000330597.5	c.410C>G	p.Ala137Gly	missense_variant	3/3	1	NM_000559.3	P1
HBG1	ENST00000648735.1	n.1341C>G		non_coding_transcript_exon_variant	2/2
HBG1	ENST00000632727.1			downstream_gene_variant		3

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

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

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.00193

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000289

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00648 AC: 986 AN: 152242 Hom.: 13 Cov.: 30 AF XY: 0.00617 AC XY: 459 AN XY: 74424

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00520

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

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

Jan 21, 2022

- -

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
MutationTaster	Benign	1.0	N
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

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