1-39626963-C-A

Variant summary

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

The NM_014571.4(HEYL):​c.531G>T​(p.Trp177Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00079 in 1,614,034 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00078 ( 2 hom. )

Consequence

HEYL
NM_014571.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.59
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18370086).
BS2
High AC in GnomAd4 at 128 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HEYLNM_014571.4 linkc.531G>T p.Trp177Cys missense_variant Exon 5 of 5 ENST00000372852.4 NP_055386.2 Q9NQ87
HEYLXM_005270745.4 linkc.447G>T p.Trp149Cys missense_variant Exon 5 of 5 XP_005270802.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEYLENST00000372852.4 linkc.531G>T p.Trp177Cys missense_variant Exon 5 of 5 1 NM_014571.4 ENSP00000361943.3 Q9NQ87

Frequencies

GnomAD3 genomes
AF:
0.000841
AC:
128
AN:
152146
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00141
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000686
AC:
172
AN:
250634
Hom.:
0
AF XY:
0.000738
AC XY:
100
AN XY:
135518
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000521
Gnomad ASJ exome
AF:
0.000995
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.00118
Gnomad OTH exome
AF:
0.00114
GnomAD4 exome
AF:
0.000785
AC:
1147
AN:
1461770
Hom.:
2
Cov.:
33
AF XY:
0.000781
AC XY:
568
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000626
Gnomad4 ASJ exome
AF:
0.000766
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.000922
Gnomad4 OTH exome
AF:
0.000927
GnomAD4 genome
AF:
0.000841
AC:
128
AN:
152264
Hom.:
0
Cov.:
33
AF XY:
0.000698
AC XY:
52
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00141
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.00137
Hom.:
0
Bravo
AF:
0.000827
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.000610
AC:
74
EpiCase
AF:
0.00185
EpiControl
AF:
0.00172

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 01, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.531G>T (p.W177C) alteration is located in exon 5 (coding exon 5) of the HEYL gene. This alteration results from a G to T substitution at nucleotide position 531, causing the tryptophan (W) at amino acid position 177 to be replaced by a cysteine (C). 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
0.63
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.55
D
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
2.0
M
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.3
D
REVEL
Uncertain
0.31
Sift
Benign
0.065
T
Sift4G
Benign
0.082
T
Polyphen
1.0
D
Vest4
0.58
MutPred
0.48
Gain of catalytic residue at P176 (P = 0.0097);
MVP
0.85
MPC
0.85
ClinPred
0.22
T
GERP RS
5.0
Varity_R
0.44
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs138365730; hg19: chr1-40092635; API