Genetic Variant HEY1:p.Asp114Asn (chr8-79765763-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_012258.4(HEY1):c.340G>A(p.Asp114Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000443 in 1,603,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

HEY1
NM_012258.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Publications

3 publications found

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:

LINC01607 (HGNC:51660): (long intergenic non-protein coding RNA 1607)

LINC01607 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15901002).

BS2

High AC in GnomAd4 at 55 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012258.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEY1	NM_012258.4	MANE Select	c.340G>A	p.Asp114Asn	missense	Exon 5 of 5	NP_036390.3
HEY1	NM_001040708.2		c.352G>A	p.Asp118Asn	missense	Exon 5 of 5	NP_001035798.1	Q9Y5J3-2
HEY1	NM_001282851.2		c.70G>A	p.Asp24Asn	missense	Exon 2 of 2	NP_001269780.1	B4DEI9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEY1	ENST00000354724.8	TSL:1 MANE Select	c.340G>A	p.Asp114Asn	missense	Exon 5 of 5	ENSP00000346761.3	Q9Y5J3-1
HEY1	ENST00000337919.9	TSL:1	c.352G>A	p.Asp118Asn	missense	Exon 5 of 5	ENSP00000338272.5	Q9Y5J3-2
HEY1	ENST00000435063.4	TSL:1	n.151G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000528

AC:

131

AN:

248130

AF XY:

0.000602

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.000704

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000420

Gnomad NFE exome

AF:

0.000991

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000452

AC:

655

AN:

1450632

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

319

AN XY:

719352

show subpopulations

African (AFR)

AF:

0.000181

AC:

AN:

33080

American (AMR)

AF:

0.0000680

AC:

AN:

44110

Ashkenazi Jewish (ASJ)

AF:

0.000424

AC:

AN:

25964

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39360

South Asian (SAS)

AF:

0.0000814

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.000584

AC:

AN:

53110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.000525

AC:

579

AN:

1103478

Other (OTH)

AF:

0.000284

AC:

AN:

59796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.000361

AC:

AN:

152386

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41598

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.000344

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000659

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.052

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.70

MutationAssessor

Benign

2.0

PhyloP100

7.6

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.28

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.46

MVP

0.50

MPC

1.3

ClinPred

0.29

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.85

gMVP

0.67

Mutation Taster

=22/78

disease causing

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over