rs879253737

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM4_SupportingPP5_Moderate

The NM_018063.5(HELLS):c.2400_2402delGTT(p.Leu801del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000688 in 1,598,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

HELLS
NM_018063.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.60

Publications

2 publications found

Variant links:

Genes affected

HELLS (HGNC:4861): (helicase, lymphoid specific) This gene encodes a lymphoid-specific helicase. Other helicases function in processes involving DNA strand separation, including replication, repair, recombination, and transcription. This protein is thought to be involved with cellular proliferation and may play a role in leukemogenesis. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2014]

HELLS Gene-Disease associations (from GenCC):

immunodeficiency-centromeric instability-facial anomalies syndrome 4
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
immunodeficiency-centromeric instability-facial anomalies syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HELLS links:

ENSG00000244332 (HGNC:):

ENSG00000244332 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_018063.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 10-94597082-AGTT-A is Pathogenic according to our data. Variant chr10-94597082-AGTT-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 225528.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELLS	NM_018063.5 link	c.2400_2402delGTT	p.Leu801del	disruptive_inframe_deletion	Exon 21 of 22	ENST00000348459.10	NP_060533.2	Q9NRZ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELLS	ENST00000348459.10 link	c.2400_2402delGTT	p.Leu801del	disruptive_inframe_deletion	Exon 21 of 22	1	NM_018063.5	ENSP00000239027.7		Q9NRZ9-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249770

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000691

AC:

AN:

1446562

Hom.:

AF XY:

0.00000694

AC XY:

AN XY:

720522

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.0000225

AC:

AN:

44482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25974

East Asian (EAS)

AF:

0.00

AC:

AN:

39478

South Asian (SAS)

AF:

0.00

AC:

AN:

85418

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000455

AC:

AN:

1099150

Other (OTH)

AF:

0.00

AC:

AN:

59858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.430

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 4

Pathogenic:1

Jul 19, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.2400_2402del, results in the deletion of 1 amino acid(s) of the HELLS protein (p.Leu801del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs767250687, gnomAD 0.009%). This variant has been observed in individual(s) with Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome (PMID: 26216346, 30511102, 35904121). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225528). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.6

Mutation Taster

=59/41

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over