Genetic Variant HELT:p.Glu50Asp (chr4-185019078-A-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000338875.5(HELT):c.150A>C(p.Glu50Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.000060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HELT
ENST00000338875.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.418

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050658256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELT	NM_001300781.2 link	c.27+123A>C		intron_variant	Intron 1 of 3	ENST00000515777.6	NP_001287710.1	A6NFD8-3
HELT	XM_017008186.2 link	c.150A>C	p.Glu50Asp	missense_variant	Exon 1 of 4		XP_016863675.2
HELT	NM_001300782.2 link	c.27+123A>C		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.150A>C	p.Glu50Asp	missense_variant	Exon 1 of 4	1		ENSP00000343464.4	A0A087WSW0
HELT	ENST00000515777.6 link	c.27+123A>C		intron_variant	Intron 1 of 3	1	NM_001300781.2	ENSP00000426033.1	A6NFD8-3
HELT	ENST00000505610.5 link	c.27+123A>C		intron_variant	Intron 1 of 3	1		ENSP00000422140.1	A6NFD8-4
HELT	ENST00000513599.1 link	n.115+123A>C		intron_variant	Intron 1 of 2	1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150616

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.000293

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000445

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000138

AC:

AN:

1449972

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

721470

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000127

Gnomad4 OTH exome

AF:

0.0000671

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000597

AC:

AN:

150740

Hom.:

Cov.:

AF XY:

0.0000814

AC XY:

AN XY:

73672

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000199

Gnomad4 SAS

AF:

0.000212

Gnomad4 FIN

AF:

0.000293

Gnomad4 NFE

AF:

0.0000445

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.150A>C (p.E50D) alteration is located in exon 1 (coding exon 1) of the HELT gene. This alteration results from a A to C substitution at nucleotide position 150, causing the glutamic acid (E) at amino acid position 50 to be replaced by an aspartic acid (D). 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

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.6

DANN

Benign

0.74

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.35

M_CAP

Benign

0.0029

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.83

REVEL

Benign

0.029

Sift

Benign

0.33

Sift4G

Benign

0.58

Vest4

0.20

MutPred

0.12

Gain of MoRF binding (P = 0.122);

MVP

0.18

MPC

0.31

ClinPred

0.14

GERP RS

-1.4

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