11-5249571-A-C

Variant names:

• chr11-5249571-A-C
• rs35700518
• NM_000559.3:c.112T>G
• HBG1 p.Trp38Gly

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000559.3(HBG1):​c.112T>G​(p.Trp38Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., cov: 6)
  • Exomes 𝑓: 0.0000088 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 1.99
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24532092).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000559.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	NM_000559.3	MANE Select	c.112T>G	p.Trp38Gly	missense	Exon 2 of 3	NP_000550.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.112T>G	p.Trp38Gly	missense	Exon 2 of 3	ENSP00000327431.4	P69891
	ENSG00000284931	ENST00000642908.1		c.316-1084T>G		intron	N/A	ENSP00000495346.1	A0AA75LVZ2
	HBG1	ENST00000632727.1	TSL:3	c.74T>G	p.Met25Arg	missense	Exon 2 of 3	ENSP00000488759.1	A0A0J9YYA3

Frequencies

GnomAD3 genomes AF: 0.0000186 AC: 1 AN: 53882 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000737

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 2 AN: 123856 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000394

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000884 AC: 7 AN: 792202 Hom.: 1 Cov.: 11 AF XY: 0.00000991 AC XY: 4 AN XY: 403604

African (AFR) AF: 0.00 AC: 0 AN: 17868

American (AMR) AF: 0.00 AC: 0 AN: 32766

Ashkenazi Jewish (ASJ) AF: 0.000264 AC: 5 AN: 18966

East Asian (EAS) AF: 0.00 AC: 0 AN: 31246

South Asian (SAS) AF: 0.00 AC: 0 AN: 59048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2856

European-Non Finnish (NFE) AF: 0.00000361 AC: 2 AN: 553684

Other (OTH) AF: 0.00 AC: 0 AN: 36158

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000186 AC: 1 AN: 53882 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 25292

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

African (AFR) AF: 0.00 AC: 0 AN: 12786

American (AMR) AF: 0.00 AC: 0 AN: 4468

Ashkenazi Jewish (ASJ) AF: 0.000737 AC: 1 AN: 1356

East Asian (EAS) AF: 0.00 AC: 0 AN: 1894

South Asian (SAS) AF: 0.00 AC: 0 AN: 1408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 26158

Other (OTH) AF: 0.00 AC: 0 AN: 654

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	HEMOGLOBIN F (COBB) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Benign	0.97
Eigen	Benign	0.18
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.71	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.25	T
PhyloP100		2.0
PromoterAI		0.018	Neutral
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35700518;

hg19: chr11-5270801;