Genetic Variant NES:p.Pro1275Leu (chr1-156670364-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006617.2(NES):c.3824C>T(p.Pro1275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,607,838 control chromosomes in the GnomAD database, including 345,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34899 hom., cov: 32)

Exomes 𝑓: 0.65 ( 310229 hom. )

Consequence

NES
NM_006617.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.24

Publications

41 publications found

Variant links:

Genes affected

NES (HGNC:7756): (nestin) This gene encodes a member of the intermediate filament protein family and is expressed primarily in nerve cells. [provided by RefSeq, Sep 2011]

NES links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.881236E-7).

BP6

Variant 1-156670364-G-A is Benign according to our data. Variant chr1-156670364-G-A is described in CliVar as Benign. Clinvar id is 1238056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156670364-G-A is described in CliVar as Benign. Clinvar id is 1238056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156670364-G-A is described in CliVar as Benign. Clinvar id is 1238056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NES	NM_006617.2 link	c.3824C>T	p.Pro1275Leu	missense_variant	Exon 4 of 4	ENST00000368223.4	NP_006608.1	P48681Q9H6U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NES	ENST00000368223.4 link	c.3824C>T	p.Pro1275Leu	missense_variant	Exon 4 of 4	1	NM_006617.2	ENSP00000357206.3		P48681

Frequencies

GnomAD3 genomes

AF:

0.675

AC:

102537

AN:

151902

Hom.:

34873

Cov.:

show subpopulations

Gnomad AFR

AF:

0.696

Gnomad AMI

AF:

0.571

Gnomad AMR

AF:

0.724

Gnomad ASJ

AF:

0.709

Gnomad EAS

AF:

0.861

Gnomad SAS

AF:

0.638

Gnomad FIN

AF:

0.653

Gnomad MID

AF:

0.718

Gnomad NFE

AF:

0.642

Gnomad OTH

AF:

0.692

GnomAD2 exomes

AF:

0.677

AC:

166801

AN:

246448

AF XY:

0.670

show subpopulations

Gnomad AFR exome

AF:

0.693

Gnomad AMR exome

AF:

0.714

Gnomad ASJ exome

AF:

0.711

Gnomad EAS exome

AF:

0.865

Gnomad FIN exome

AF:

0.663

Gnomad NFE exome

AF:

0.645

Gnomad OTH exome

AF:

0.680

GnomAD4 exome

AF:

0.651

AC:

948281

AN:

1455820

Hom.:

310229

Cov.:

AF XY:

0.650

AC XY:

470479

AN XY:

723766

show subpopulations

African (AFR)

AF:

0.694

AC:

23134

AN:

33318

American (AMR)

AF:

0.718

AC:

31601

AN:

44016

Ashkenazi Jewish (ASJ)

AF:

0.710

AC:

18149

AN:

25572

East Asian (EAS)

AF:

0.809

AC:

32080

AN:

39646

South Asian (SAS)

AF:

0.626

AC:

53471

AN:

85354

European-Finnish (FIN)

AF:

0.662

AC:

35198

AN:

53138

Middle Eastern (MID)

AF:

0.625

AC:

3589

AN:

5742

European-Non Finnish (NFE)

AF:

0.641

AC:

710539

AN:

1108954

Other (OTH)

AF:

0.674

AC:

40520

AN:

60080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

20965

41930

62896

83861

104826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18874

37748

56622

75496

94370

<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:

0.675

AC:

102607

AN:

152018

Hom.:

34899

Cov.:

AF XY:

0.678

AC XY:

50404

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.695

AC:

28825

AN:

41460

American (AMR)

AF:

0.725

AC:

11065

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.709

AC:

2461

AN:

3472

East Asian (EAS)

AF:

0.861

AC:

4429

AN:

5144

South Asian (SAS)

AF:

0.639

AC:

3081

AN:

4822

European-Finnish (FIN)

AF:

0.653

AC:

6923

AN:

10600

Middle Eastern (MID)

AF:

0.721

AC:

212

AN:

294

European-Non Finnish (NFE)

AF:

0.642

AC:

43623

AN:

67930

Other (OTH)

AF:

0.695

AC:

1467

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1769

3537

5306

7074

8843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

808

1616

2424

3232

4040

<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:

0.659

Hom.:

146233

Bravo

AF:

0.683

TwinsUK

AF:

0.628

AC:

2330

ALSPAC

AF:

0.635

AC:

2446

ESP6500AA

AF:

0.693

AC:

3055

ESP6500EA

AF:

0.643

AC:

5527

ExAC

AF:

0.671

AC:

81471

Asia WGS

AF:

0.775

AC:

2688

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 24, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18724036) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.094

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.34

MetaRNN

Benign

5.9e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

1.2

PrimateAI

Benign

0.41

PROVEAN

Benign

3.3

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.054

MPC

0.057

ClinPred

0.0052

GERP RS

5.0

Varity_R

0.040

gMVP

0.017

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over