chr10-94562813-T-TATGAGGAA

Variant names:

• chr10-94562813-T-TATGAGGAA
• rs879253736
• NM_018063.5:c.374_381dupTGAGGAAA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_018063.5(HELLS):​c.374_381dupTGAGGAAA​(p.Lys128fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HELLS NM_018063.5 frameshift, stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.12
• Publications: 1 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-94562813-T-TATGAGGAA is Pathogenic according to our data. Variant chr10-94562813-T-TATGAGGAA is described in ClinVar as Pathogenic. ClinVar VariationId is 225527.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELLS	NM_018063.5	MANE Select	c.374_381dupTGAGGAAA	p.Lys128fs	frameshift stop_gained	Exon 6 of 22	NP_060533.2
	HELLS	NM_001289067.2		c.374_381dupTGAGGAAA	p.Lys128fs	frameshift stop_gained	Exon 6 of 23	NP_001275996.1
	HELLS	NM_001289068.2		c.326_333dupTGAGGAAA	p.Lys112fs	frameshift stop_gained	Exon 6 of 22	NP_001275997.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELLS	ENST00000348459.10	TSL:1 MANE Select	c.374_381dupTGAGGAAA	p.Lys128fs	frameshift stop_gained	Exon 6 of 22	ENSP00000239027.7
	HELLS	ENST00000394036.6	TSL:1	c.374_381dupTGAGGAAA	p.Lys128fs	frameshift stop_gained	Exon 6 of 23	ENSP00000377601.2
	HELLS	ENST00000394045.6	TSL:1	c.374_381dupTGAGGAAA	p.Lys128fs	frameshift stop_gained	Exon 6 of 20	ENSP00000377609.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs879253736; hg19: chr10-96322570;