Genetic Variant HEYL:p.Arg218Gln (chr1-39626841-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014571.4(HEYL):c.653G>A(p.Arg218Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000666 in 1,576,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

HEYL
NM_014571.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Variant links:

Genes affected

HEYL (HGNC:4882): (hes related family bHLH transcription factor with YRPW motif like) This gene encodes a member of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcription factors. The sequence of the encoded protein contains a conserved bHLH and orange domain, but its YRPW motif has diverged from other HESR family members. It is thought to be an effector of Notch signaling and a regulator of cell fate decisions. Alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

HEYL links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15970644).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEYL	NM_014571.4 link	c.653G>A	p.Arg218Gln	missense_variant	Exon 5 of 5	ENST00000372852.4	NP_055386.2	Q9NQ87
HEYL	XM_005270745.4 link	c.569G>A	p.Arg190Gln	missense_variant	Exon 5 of 5		XP_005270802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEYL	ENST00000372852.4 link	c.653G>A	p.Arg218Gln	missense_variant	Exon 5 of 5	1	NM_014571.4	ENSP00000361943.3		Q9NQ87

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000157

AC:

AN:

191598

Hom.:

AF XY:

0.0000196

AC XY:

AN XY:

102108

show subpopulations

Gnomad AFR exome

AF:

0.0000845

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000243

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000667

AC:

AN:

1424646

Hom.:

Cov.:

AF XY:

0.0000724

AC XY:

AN XY:

704906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.0000842

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.653G>A (p.R218Q) alteration is located in exon 5 (coding exon 5) of the HEYL gene. This alteration results from a G to A substitution at nucleotide position 653, causing the arginine (R) at amino acid position 218 to be replaced by a glutamine (Q). 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

Benign

0.082

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.027

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.64

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.87

REVEL

Benign

0.27

Sift

Benign

0.21

Sift4G

Benign

0.23

Polyphen

1.0

Vest4

0.31

MVP

0.77

MPC

0.71

ClinPred

0.41

GERP RS

5.0

Varity_R

0.12

gMVP

0.67

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