Variant 8-79765388-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_012258.4(HEY1):c.715C>T(p.Pro239Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000562 in 1,601,284 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HEY1
NM_012258.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.96

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09492272).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEY1	NM_012258.4 link	c.715C>T	p.Pro239Ser	missense_variant	5/5	ENST00000354724.8	NP_036390.3	Q9Y5J3-1
HEY1	NM_001040708.2 link	c.727C>T	p.Pro243Ser	missense_variant	5/5		NP_001035798.1	Q9Y5J3-2
HEY1	NM_001282851.2 link	c.445C>T	p.Pro149Ser	missense_variant	2/2		NP_001269780.1	Q9Y5J3B4DEI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEY1	ENST00000354724.8 link	c.715C>T	p.Pro239Ser	missense_variant	5/5	1	NM_012258.4	ENSP00000346761.3		Q9Y5J3-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1449048

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719860

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

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:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.715C>T (p.P239S) alteration is located in exon 5 (coding exon 5) of the HEY1 gene. This alteration results from a C to T substitution at nucleotide position 715, causing the proline (P) at amino acid position 239 to be replaced by a serine (S). 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

0.063

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.70

D;.;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.095

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.069

Sift

Benign

0.084

T;T;D

Sift4G

Benign

0.11

T;T;T

Polyphen

0.027

B;B;.

Vest4

0.055

MutPred

0.19

Gain of phosphorylation at P239 (P = 0.0318);.;.;

MVP

0.22

MPC

0.52

ClinPred

0.71

GERP RS

4.9

Varity_R

0.099

gMVP

0.53

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