Genetic Variant HEY1:p.Phe271Leu (chr8-79765292-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_012258.4(HEY1):c.811T>C(p.Phe271Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00825 in 1,557,002 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0054 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0086 ( 73 hom. )

Consequence

HEY1
NM_012258.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.96

Variant links:

Genes affected

HEY1 (HGNC:4880): (hes related family bHLH transcription factor with YRPW motif 1) This gene encodes a nuclear protein belonging to the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcriptional repressors. Expression of this gene is induced by the Notch and c-Jun signal transduction pathways. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

HEY1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053284466).

BP6

Variant 8-79765292-A-G is Benign according to our data. Variant chr8-79765292-A-G is described in ClinVar as [Benign]. Clinvar id is 3033148.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 820 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEY1	NM_012258.4 link	c.811T>C	p.Phe271Leu	missense_variant	Exon 5 of 5	ENST00000354724.8	NP_036390.3	Q9Y5J3-1
HEY1	NM_001040708.2 link	c.823T>C	p.Phe275Leu	missense_variant	Exon 5 of 5		NP_001035798.1	Q9Y5J3-2
HEY1	NM_001282851.2 link	c.541T>C	p.Phe181Leu	missense_variant	Exon 2 of 2		NP_001269780.1	Q9Y5J3B4DEI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEY1	ENST00000354724.8 link	c.811T>C	p.Phe271Leu	missense_variant	Exon 5 of 5	1	NM_012258.4	ENSP00000346761.3		Q9Y5J3-1

Frequencies

GnomAD3 genomes

AF:

0.00539

AC:

820

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00804

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00531

AC:

866

AN:

163070

Hom.:

AF XY:

0.00503

AC XY:

432

AN XY:

85934

show subpopulations

Gnomad AFR exome

AF:

0.000834

Gnomad AMR exome

AF:

0.00164

Gnomad ASJ exome

AF:

0.00607

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000301

Gnomad FIN exome

AF:

0.0107

Gnomad NFE exome

AF:

0.00882

Gnomad OTH exome

AF:

0.00530

GnomAD4 exome

AF:

0.00856

AC:

12029

AN:

1404666

Hom.:

Cov.:

AF XY:

0.00814

AC XY:

5646

AN XY:

693226

show subpopulations

Gnomad4 AFR exome

AF:

0.00130

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.00679

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000402

Gnomad4 FIN exome

AF:

0.0125

Gnomad4 NFE exome

AF:

0.00979

Gnomad4 OTH exome

AF:

0.00859

GnomAD4 genome

AF:

0.00538

AC:

820

AN:

152336

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

400

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0103

Gnomad4 NFE

AF:

0.00804

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00749

Hom.:

Bravo

AF:

0.00494

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00679

AC:

ExAC

AF:

0.00306

AC:

346

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEY1-related disorder

Benign:1

Apr 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.35

T;.;T

Eigen

Benign

-0.096

Eigen_PC

Benign

0.080

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0053

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.56

N;N;N

REVEL

Benign

0.036

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.0060

B;B;.

Vest4

0.19

MutPred

0.28

Loss of loop (P = 0.0603);.;.;

MVP

0.31

MPC

0.61

ClinPred

0.022

GERP RS

4.6

Varity_R

0.12

gMVP

0.62

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