rs140316223

Variant names:

• chr10-94562729-T-A
• rs140316223
• NM_018063.5:c.370+2T>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_018063.5(HELLS):​c.370+2T>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000977 in 1,432,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003439650: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. PMID:26216346".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: HELLS NM_018063.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.00
• 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: ClinGen, Labcorp Genetics (formerly Invitae)
• immunodeficiency-centromeric instability-facial anomalies syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014700039 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of -36, new splice context is: aggGTaaaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003439650: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. PMID: 26216346
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-94562729-T-A is Pathogenic according to our data. Variant chr10-94562729-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 225524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.370+2T>A		splice_donor intron	N/A	NP_060533.2
	HELLS	NM_001289067.2		c.370+2T>A		splice_donor intron	N/A	NP_001275996.1	A0A0B4J1V9
	HELLS	NM_001289068.2		c.322+2T>A		splice_donor intron	N/A	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.370+2T>A		splice_donor intron	N/A	ENSP00000239027.7	Q9NRZ9-1
	HELLS	ENST00000394036.6	TSL:1	c.370+2T>A		splice_donor intron	N/A	ENSP00000377601.2	A0A0B4J1V9
	HELLS	ENST00000394045.6	TSL:1	c.370+2T>A		splice_donor intron	N/A	ENSP00000377609.1	Q9NRZ9-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000826 AC: 2 AN: 242268 AF XY: 0.00000765

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: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000977 AC: 14 AN: 1432410 Hom.: 0 Cov.: 27 AF XY: 0.00000561 AC XY: 4 AN XY: 713312

African (AFR) AF: 0.00 AC: 0 AN: 32454

American (AMR) AF: 0.00 AC: 0 AN: 42436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 82318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.0000128 AC: 14 AN: 1091880

Other (OTH) AF: 0.00 AC: 0 AN: 59348

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Immunodeficiency-centromeric instability-facial anomalies syndrome 4 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	0.98
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs140316223;

hg19: chr10-96322486;