11-5249442-C-T

Variant names:

• chr11-5249442-C-T
• rs33947112
• NM_000559.3:c.241G>A

Variant summary

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

The NM_000559.3(HBG1):​c.241G>A​(p.Asp81Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D81Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000022 (1 hom., cov: 12)
  • Exomes 𝑓: 0.0000099 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.946
• 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=0.09425071).

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.241G>A	p.Asp81Asn	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.241G>A	p.Asp81Asn	missense	Exon 2 of 3	ENSP00000327431.4	P69891
	ENSG00000284931	ENST00000642908.1		c.316-955G>A		intron	N/A	ENSP00000495346.1	A0AA75LVZ2
	HBG1	ENST00000632727.1	TSL:3	c.*110G>A		3_prime_UTR	Exon 2 of 3	ENSP00000488759.1	A0A0J9YYA3

Frequencies

GnomAD3 genomes AF: 0.0000223 AC: 2 AN: 89528 Hom.: 1 Cov.: 12

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000589

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000991 AC: 8 AN: 807330 Hom.: 2 Cov.: 16 AF XY: 0.00000976 AC XY: 4 AN XY: 409884

African (AFR) AF: 0.00 AC: 0 AN: 19028

American (AMR) AF: 0.00 AC: 0 AN: 30950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18442

East Asian (EAS) AF: 0.000253 AC: 8 AN: 31578

South Asian (SAS) AF: 0.00 AC: 0 AN: 58034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2962

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 568578

Other (OTH) AF: 0.00 AC: 0 AN: 36314

GnomAD4 genome AF: 0.0000223 AC: 2 AN: 89528 Hom.: 1 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 43306

African (AFR) AF: 0.00 AC: 0 AN: 23334

American (AMR) AF: 0.00 AC: 0 AN: 8574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2362

East Asian (EAS) AF: 0.000589 AC: 2 AN: 3394

South Asian (SAS) AF: 0.00 AC: 0 AN: 2316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 40284

Other (OTH) AF: 0.00 AC: 0 AN: 1130

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	0.0074	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	5.9
DANN	Benign	0.76
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.55	T
PhyloP100		-0.95
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.86	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0020	B
Vest4		0.060
MutPred		0.56		Loss of ubiquitination at K83 (P = 0.0853)
MVP		0.56
MPC		1.2
ClinPred		0.014	T
GERP RS		-2.6
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.39
Mutation Taster		=48/52	disease causing

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: rs33947112; hg19: chr11-5270672; COSMIC: COSV105212801; COSMIC: COSV105212801;