ENST00000642908.1:c.316-1568T>C

Variant names:

• chr11-5250055-A-G
• rs35710727
• ENST00000642908.1:c.316-1568T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The ENST00000642908.1(ENSG00000284931):​c.316-1568T>C variant causes a intron 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 Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.000060 (0 hom., cov: 13)
• Consequence: ENSG00000284931 ENST00000642908.1 intron
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -0.569
• Publications: 1 publications found

Genes affected

ENSG00000284931 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 11-5250055-A-G is Pathogenic according to our data. Variant chr11-5250055-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 15031.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000642908.1. 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.-251T>C		upstream_gene	N/A	NP_000550.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000284931	ENST00000642908.1		c.316-1568T>C		intron	N/A	ENSP00000495346.1
	ENSG00000284931	ENST00000647543.1		c.379-1568T>C		intron	N/A	ENSP00000496470.1
	HBG1	ENST00000330597.5	TSL:1 MANE Select	c.-251T>C		upstream_gene	N/A	ENSP00000327431.4

Frequencies

GnomAD3 genomes AF: 0.0000599 AC: 3 AN: 50054 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.00

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: 0.000113

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000599 AC: 3 AN: 50054 Hom.: 0 Cov.: 13 AF XY: 0.0000810 AC XY: 2 AN XY: 24698

African (AFR) AF: 0.00 AC: 0 AN: 8856

American (AMR) AF: 0.00 AC: 0 AN: 4298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1114

East Asian (EAS) AF: 0.00 AC: 0 AN: 1118

South Asian (SAS) AF: 0.00 AC: 0 AN: 1454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 92

European-Non Finnish (NFE) AF: 0.000113 AC: 3 AN: 26630

Other (OTH) AF: 0.00 AC: 0 AN: 586

Alfa AF: 0.0000731 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

British HPFH Pathogenic:1

Dec 01, 1986

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hereditary persistence of fetal hemoglobin Pathogenic:1

Dec 01, 1986

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		-0.57
PromoterAI		0.26	Neutral

Splicing

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

Other links and lift over

dbSNP: rs35710727; hg19: chr11-5271285;