Genetic Variant HELT:p.Glu82Val (chr4-185020288-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001300781.2(HELT):c.245A>T(p.Glu82Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HELT
NM_001300781.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.16

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELT	NM_001300781.2 link	c.245A>T	p.Glu82Val	missense_variant	Exon 4 of 4	ENST00000515777.6	NP_001287710.1	A6NFD8-3
HELT	NM_001300782.2 link	c.242A>T	p.Glu81Val	missense_variant	Exon 4 of 4		NP_001287711.1	A6NFD8-4
HELT	XM_017008186.2 link	c.413A>T	p.Glu138Val	missense_variant	Exon 4 of 4		XP_016863675.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HELT	ENST00000515777.6 link	c.245A>T	p.Glu82Val	missense_variant	Exon 4 of 4	1	NM_001300781.2	ENSP00000426033.1	A6NFD8-3
HELT	ENST00000338875.5 link	c.500A>T	p.Glu167Val	missense_variant	Exon 4 of 4	1		ENSP00000343464.4	A0A087WSW0
HELT	ENST00000505610.5 link	c.242A>T	p.Glu81Val	missense_variant	Exon 4 of 4	1		ENSP00000422140.1	A6NFD8-4
HELT	ENST00000513599.1 link	n.585A>T		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250664

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461274

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500A>T (p.E167V) alteration is located in exon 4 (coding exon 4) of the HELT gene. This alteration results from a A to T substitution at nucleotide position 500, causing the glutamic acid (E) at amino acid position 167 to be replaced by a valine (V). 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

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;.;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Pathogenic

0.83

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.4

N;D;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0090

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Vest4

0.89

MutPred

0.55

.;.;Loss of disorder (P = 0.0431);

MVP

0.75

MPC

1.2

ClinPred

0.62

GERP RS

5.0

Varity_R

0.33

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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