Genetic Variant HELT:p.Arg31Leu (chr4-185019020-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000338875.5(HELT):c.92G>T(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

HELT
ENST00000338875.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.14

Variant links:

Genes affected

HELT (HGNC:33783): (helt bHLH transcription factor) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anterior/posterior pattern specification; regulation of neurogenesis; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; regulation of transcription by RNA polymerase II; and suckling behavior. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HELT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010385871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELT	NM_001300781.2 link	c.27+65G>T		intron_variant	Intron 1 of 3	ENST00000515777.6	NP_001287710.1	A6NFD8-3
HELT	XM_017008186.2 link	c.92G>T	p.Arg31Leu	missense_variant	Exon 1 of 4		XP_016863675.2
HELT	NM_001300782.2 link	c.27+65G>T		intron_variant	Intron 1 of 3		NP_001287711.1	A6NFD8-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HELT	ENST00000338875.5 link	c.92G>T	p.Arg31Leu	missense_variant	Exon 1 of 4	1		ENSP00000343464.4	A0A087WSW0
HELT	ENST00000515777.6 link	c.27+65G>T		intron_variant	Intron 1 of 3	1	NM_001300781.2	ENSP00000426033.1	A6NFD8-3
HELT	ENST00000505610.5 link	c.27+65G>T		intron_variant	Intron 1 of 3	1		ENSP00000422140.1	A6NFD8-4
HELT	ENST00000513599.1 link	n.115+65G>T		intron_variant	Intron 1 of 2	1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251054

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000152

AC:

222

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000618

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000361

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000793

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000321

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92G>T (p.R31L) alteration is located in exon 1 (coding exon 1) of the HELT gene. This alteration results from a G to T substitution at nucleotide position 92, causing the arginine (R) at amino acid position 31 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.7

DANN

Benign

0.90

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.32

M_CAP

Benign

0.0034

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.52

REVEL

Benign

0.0050

Sift

Benign

0.57

Sift4G

Uncertain

0.056

Vest4

0.24

MVP

0.085

MPC

0.42

ClinPred

0.0045

GERP RS

-1.6

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