11-5249522-G-A

Variant names:

• chr11-5249522-G-A
• rs35746147
• NM_000559.3:c.161C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000559.3(HBG1):​c.161C>T​(p.Ala54Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A54D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 8)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBG1 NM_000559.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.35
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	NM_000559.3	MANE Select	c.161C>T	p.Ala54Val	missense	Exon 2 of 3	NP_000550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.161C>T	p.Ala54Val	missense	Exon 2 of 3	ENSP00000327431.4
	ENSG00000284931	ENST00000642908.1		c.316-1035C>T		intron	N/A	ENSP00000495346.1
	HBG1	ENST00000648735.1		n.212C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000152 AC: 1 AN: 65772 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.0000606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000109 AC: 1 AN: 915718 Hom.: 0 Cov.: 17 AF XY: 0.00000216 AC XY: 1 AN XY: 462992

African (AFR) AF: 0.00 AC: 0 AN: 21600

American (AMR) AF: 0.00 AC: 0 AN: 36622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21244

East Asian (EAS) AF: 0.00 AC: 0 AN: 33934

South Asian (SAS) AF: 0.00 AC: 0 AN: 64872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3416

European-Non Finnish (NFE) AF: 0.00000153 AC: 1 AN: 651802

Other (OTH) AF: 0.00 AC: 0 AN: 40832

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000152 AC: 1 AN: 65772 Hom.: 0 Cov.: 8 AF XY: 0.0000319 AC XY: 1 AN XY: 31378

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

African (AFR) AF: 0.0000606 AC: 1 AN: 16514

American (AMR) AF: 0.00 AC: 0 AN: 5778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1656

East Asian (EAS) AF: 0.00 AC: 0 AN: 2352

South Asian (SAS) AF: 0.00 AC: 0 AN: 1760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 30408

Other (OTH) AF: 0.00 AC: 0 AN: 776

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		4.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.13
MutPred		0.90		Loss of disorder (P = 0.068)
MVP		0.99
MPC		2.3
ClinPred		0.98	D
GERP RS		2.8
PromoterAI		-0.037	Neutral
gMVP		0.23
Mutation Taster		=39/61	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: rs35746147; hg19: chr11-5270752;