rs879253733

Variant names:

• chr10-94594702-A-G
• rs879253733
• NM_018063.5:c.2096A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_018063.5(HELLS):​c.2096A>G​(p.Gln699Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HELLS NM_018063.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.29
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 10-94594702-A-G is Pathogenic according to our data. Variant chr10-94594702-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225523.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELLS	NM_018063.5	MANE Select	c.2096A>G	p.Gln699Arg	missense	Exon 19 of 22	NP_060533.2
	HELLS	NM_001289067.2		c.2234A>G	p.Gln745Arg	missense	Exon 20 of 23	NP_001275996.1	A0A0B4J1V9
	HELLS	NM_001289068.2		c.2048A>G	p.Gln683Arg	missense	Exon 19 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.2096A>G	p.Gln699Arg	missense	Exon 19 of 22	ENSP00000239027.7	Q9NRZ9-1
	HELLS	ENST00000394036.6	TSL:1	c.2234A>G	p.Gln745Arg	missense	Exon 20 of 23	ENSP00000377601.2	A0A0B4J1V9
	HELLS	ENST00000394045.6	TSL:1	c.1802A>G	p.Gln601Arg	missense	Exon 17 of 20	ENSP00000377609.1	Q9NRZ9-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Immunodeficiency-centromeric instability-facial anomalies syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.80		Gain of catalytic residue at Q699 (P = 0.1228)
MVP		0.90
MPC		1.7
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.80
gMVP		0.95
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs879253733; hg19: chr10-96354459;