chr10-94545934-C-T

Position:

• chr10-94545934-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001289071.2(HELLS):​c.-404C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,404,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: HELLS NM_001289071.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.611

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09569311).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000015 (21/1404042) while in subpopulation SAS AF= 0.000251 (20/79594). AF 95% confidence interval is 0.000166. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HELLS	NM_018063.5	c.13C>T	p.Arg5Trp	missense_variant	1/22	ENST00000348459.10	NP_060533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HELLS	ENST00000348459.10	c.13C>T	p.Arg5Trp	missense_variant	1/22	1	NM_018063.5	ENSP00000239027.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000497 AC: 8 AN: 160848 Hom.: 0 AF XY: 0.0000587 AC XY: 5 AN XY: 85110

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 SAS exome AF: 0.000345

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 21 AN: 1404042 Hom.: 0 Cov.: 31 AF XY: 0.0000202 AC XY: 14 AN XY: 692890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000275 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2024

The c.13C>T (p.R5W) alteration is located in exon 1 (coding exon 1) of the HELLS gene. This alteration results from a C to T substitution at nucleotide position 13, causing the arginine (R) at amino acid position 5 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

ClinVar contains an entry for this variant (Variation ID: 1491475). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5 of the HELLS protein (p.Arg5Trp). This variant is present in population databases (rs778232211, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HELLS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.085	N
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.096	T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.1	.;L;.;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	.;N;D;N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	.;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.83, 0.99	.;P;.;D
Vest4		0.28
MutPred		0.16		Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP		0.47
MPC		0.93
ClinPred		0.20	T
GERP RS		3.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.17
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs778232211; hg19: chr10-96305691;