Genetic Variant HES5:p.Ala150Thr (chr1-2529522-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001010926.4(HES5):c.448G>A(p.Ala150Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,050,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A150D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

HES5
NM_001010926.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.156

Publications

0 publications found

Variant links:

Genes affected

HES5 (HGNC:19764): (hes family bHLH transcription factor 5) This gene encodes a member of a family of basic helix-loop-helix transcriptional repressors. The protein product of this gene, which is activated downstream of the Notch pathway, regulates cell differentiation in multiple tissues. Disruptions in the normal expression of this gene have been associated with developmental diseases and cancer. [provided by RefSeq, Dec 2008]

HES5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10827747).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010926.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HES5	NM_001010926.4	MANE Select	c.448G>A	p.Ala150Thr	missense	Exon 3 of 3	NP_001010926.1	Q5TA89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HES5	ENST00000378453.4	TSL:1 MANE Select	c.448G>A	p.Ala150Thr	missense	Exon 3 of 3	ENSP00000367714.3	Q5TA89

Frequencies

GnomAD3 genomes

AF:

0.000170

AC:

AN:

147464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000588

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000675

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

466

AF XY:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000321

AC:

AN:

902984

Hom.:

Cov.:

AF XY:

0.0000379

AC XY:

AN XY:

422270

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000459

AC:

AN:

17428

American (AMR)

AF:

0.00

AC:

AN:

3192

Ashkenazi Jewish (ASJ)

AF:

0.000131

AC:

AN:

7618

East Asian (EAS)

AF:

0.00

AC:

AN:

10518

South Asian (SAS)

AF:

0.00

AC:

AN:

17802

European-Finnish (FIN)

AF:

0.000242

AC:

AN:

8260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2042

European-Non Finnish (NFE)

AF:

0.0000211

AC:

AN:

804282

Other (OTH)

AF:

0.0000314

AC:

AN:

31842

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000054734), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.313

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000169

AC:

AN:

147570

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

71946

show subpopulations

African (AFR)

AF:

0.000586

AC:

AN:

40944

American (AMR)

AF:

0.0000674

AC:

AN:

14844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

5102

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66382

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000142

Hom.:

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

Benign

0.079

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.7

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.20

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.085

M_CAP

Benign

0.044

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.14

PhyloP100

0.16

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.33

REVEL

Benign

0.13

Sift

Benign

0.42

Sift4G

Benign

0.61

Polyphen

0.72

Vest4

0.12

MutPred

0.21

Gain of glycosylation at A150 (P = 0.0012)

MVP

0.27

MPC

0.13

ClinPred

0.19

GERP RS

1.1

Varity_R

0.065

gMVP

0.45

Mutation Taster

=99/1

polymorphism

(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