rs879253737

Variant names:

• chr10-94597082-AGTT-A
• rs879253737
• NM_018063.5:c.2400_2402delGTT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.60
• Publications: 2 publications found

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

ENSG00000244332 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018063.5. 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
	HELLS	NM_018063.5	MANE Select	c.2400_2402delGTT	p.Leu801del	disruptive_inframe_deletion	Exon 21 of 22	NP_060533.2
	HELLS	NM_001289067.2		c.2538_2540delGTT	p.Leu847del	disruptive_inframe_deletion	Exon 22 of 23	NP_001275996.1	A0A0B4J1V9
	HELLS	NM_001289068.2		c.2352_2354delGTT	p.Leu785del	disruptive_inframe_deletion	Exon 21 of 22	NP_001275997.1	Q9NRZ9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELLS	ENST00000348459.10	TSL:1 MANE Select	c.2400_2402delGTT	p.Leu801del	disruptive_inframe_deletion	Exon 21 of 22	ENSP00000239027.7	Q9NRZ9-1
	HELLS	ENST00000394036.6	TSL:1	c.2538_2540delGTT	p.Leu847del	disruptive_inframe_deletion	Exon 22 of 23	ENSP00000377601.2	A0A0B4J1V9
	HELLS	ENST00000394045.6	TSL:1	c.2106_2108delGTT	p.Leu703del	disruptive_inframe_deletion	Exon 19 of 20	ENSP00000377609.1	Q9NRZ9-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

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: 3 AN: 249770 AF XY: 0.0000148

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: 10 AN: 1446562 Hom.: 0 AF XY: 0.00000694 AC XY: 5 AN XY: 720522

African (AFR) AF: 0.00 AC: 0 AN: 33144

American (AMR) AF: 0.0000225 AC: 1 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 85418

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000455 AC: 5 AN: 1099150

Other (OTH) AF: 0.00 AC: 0 AN: 59858

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Immunodeficiency-centromeric instability-facial anomalies syndrome 4 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=59/41	disease causing (ClinVar)

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: rs879253737; hg19: chr10-96356839; COSMIC: COSV106089227; COSMIC: COSV106089227;