10-94545923-T-C

Position:

chr10-94545923-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_018063.5(HELLS):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 1,555,604 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 7 hom. )

Consequence

HELLS
NM_018063.5 start_lost

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.23

Variant links:

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 links:

HELLS (HGNC:):

HELLS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

BP6

Variant 10-94545923-T-C is Benign according to our data. Variant chr10-94545923-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 716400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00447 (681/152318) while in subpopulation AFR AF= 0.0152 (633/41566). AF 95% confidence interval is 0.0142. There are 6 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HELLS	NM_018063.5 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/22	ENST00000348459.10	NP_060533.2	Q9NRZ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HELLS	ENST00000348459.10 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/22	1	NM_018063.5	ENSP00000239027.7		Q9NRZ9-1

Frequencies

GnomAD3 genomes

AF:

0.00448

AC:

682

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00128

AC:

204

AN:

159870

Hom.:

AF XY:

0.00111

AC XY:

AN XY:

84506

show subpopulations

Gnomad AFR exome

AF:

0.0168

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000866

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000209

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000621

AC:

871

AN:

1403286

Hom.:

Cov.:

AF XY:

0.000598

AC XY:

414

AN XY:

692472

show subpopulations

Gnomad4 AFR exome

AF:

0.0180

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000880

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000114

Gnomad4 OTH exome

AF:

0.00168

GnomAD4 genome

AF:

0.00447

AC:

681

AN:

152318

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

319

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0152

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000808

Hom.:

Bravo

AF:

0.00515

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.00129

AC:

140

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

Immunodeficiency-centromeric instability-facial anomalies syndrome 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 05, 2022

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 1.5% (633/41444) including 6 homozygotes (https://gnomad.broadinstitute.org/variant/10-94545923-T-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:716400). Evolutionary conservation and computational predictive tools for this variant are unclear. This variant alters the initiation codon (Methionine), potentially resulting in loss of the protein. However, the presence of this variant in controls, particularly homozygotes argues against a pathogenic impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.023

T;T;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.90

D;D;D;D

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.35

PROVEAN

Benign

-0.79

.;N;N;N

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.72, 0.95

.;P;.;P

Vest4

0.79

MVP

0.82

ClinPred

0.18

GERP RS

3.3

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.91

gMVP

0.43

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over