Genetic Variant HELT:p.Ser46Phe (chr4-185019751-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001300781.2(HELT):c.137C>T(p.Ser46Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S46C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HELT
NM_001300781.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.84

Publications

2 publications found

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:

ENSG00000301811 (HGNC:):

ENSG00000301811 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300781.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELT	NM_001300781.2	MANE Select	c.137C>T	p.Ser46Phe	missense	Exon 3 of 4	NP_001287710.1	A6NFD8-3
	HELT	NM_001300782.2		c.137C>T	p.Ser46Phe	missense	Exon 3 of 4	NP_001287711.1	A6NFD8-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HELT	ENST00000515777.6	TSL:1 MANE Select	c.137C>T	p.Ser46Phe	missense	Exon 3 of 4	ENSP00000426033.1	A6NFD8-3
HELT	ENST00000338875.5	TSL:1	c.392C>T	p.Ser131Phe	missense	Exon 3 of 4	ENSP00000343464.4	A0A087WSW0
HELT	ENST00000505610.5	TSL:1	c.137C>T	p.Ser46Phe	missense	Exon 3 of 4	ENSP00000422140.1	A6NFD8-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461086

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726836

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111950

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

1.1

PhyloP100

4.8

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Vest4

0.66

MutPred

0.76

Loss of disorder (P = 0.0187)

MVP

0.88

MPC

1.1

ClinPred

1.0

GERP RS

4.9

Varity_R

0.89

gMVP

0.47

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over