6-32222613-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_004557.4(NOTCH4):c.349A>C(p.Lys117Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,601,760 control chromosomes in the GnomAD database, including 116,051 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 0.36 ( 10078 hom., cov: 32)

Exomes 𝑓: 0.38 ( 105973 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.03

Publications

75 publications found

Variant links:

Genes affected

NOTCH4 (HGNC:7884): (notch receptor 4) This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

NOTCH4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.202361E-4).

BP6

Variant 6-32222613-T-G is Benign according to our data. Variant chr6-32222613-T-G is described in ClinVar as Benign. ClinVar VariationId is 1294880.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004557.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NOTCH4	NM_004557.4	MANE Select	c.349A>C	p.Lys117Gln	missense	Exon 3 of 30	NP_004548.3
NOTCH4	NR_134949.2		n.488A>C		non_coding_transcript_exon	Exon 3 of 30
NOTCH4	NR_134950.2		n.488A>C		non_coding_transcript_exon	Exon 3 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.349A>C	p.Lys117Gln	missense	Exon 3 of 30	ENSP00000364163.3
NOTCH4	ENST00000473562.1	TSL:1	n.478A>C		non_coding_transcript_exon	Exon 3 of 11
NOTCH4	ENST00000883244.1		c.349A>C	p.Lys117Gln	missense	Exon 3 of 30	ENSP00000553303.1

Frequencies

GnomAD3 genomes

AF:

0.360

AC:

54623

AN:

151886

Hom.:

10078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.377

Gnomad AMI

AF:

0.328

Gnomad AMR

AF:

0.286

Gnomad ASJ

AF:

0.366

Gnomad EAS

AF:

0.492

Gnomad SAS

AF:

0.406

Gnomad FIN

AF:

0.312

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.361

Gnomad OTH

AF:

0.348

GnomAD2 exomes

AF:

0.352

AC:

84293

AN:

239624

AF XY:

0.355

show subpopulations

Gnomad AFR exome

AF:

0.382

Gnomad AMR exome

AF:

0.270

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.462

Gnomad FIN exome

AF:

0.307

Gnomad NFE exome

AF:

0.355

Gnomad OTH exome

AF:

0.347

GnomAD4 exome

AF:

0.379

AC:

549427

AN:

1449756

Hom.:

105973

Cov.:

AF XY:

0.378

AC XY:

272786

AN XY:

721400

show subpopulations

African (AFR)

AF:

0.376

AC:

12231

AN:

32542

American (AMR)

AF:

0.274

AC:

11063

AN:

40388

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

9651

AN:

25456

East Asian (EAS)

AF:

0.505

AC:

19950

AN:

39498

South Asian (SAS)

AF:

0.374

AC:

31681

AN:

84768

European-Finnish (FIN)

AF:

0.306

AC:

16343

AN:

53336

Middle Eastern (MID)

AF:

0.305

AC:

1734

AN:

5690

European-Non Finnish (NFE)

AF:

0.383

AC:

424444

AN:

1108182

Other (OTH)

AF:

0.373

AC:

22330

AN:

59896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

18992

37983

56975

75966

94958

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13636

27272

40908

54544

68180

<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:

0.360

AC:

54652

AN:

152004

Hom.:

10078

Cov.:

AF XY:

0.356

AC XY:

26465

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.376

AC:

15602

AN:

41448

American (AMR)

AF:

0.287

AC:

4383

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

1270

AN:

3472

East Asian (EAS)

AF:

0.493

AC:

2530

AN:

5132

South Asian (SAS)

AF:

0.406

AC:

1958

AN:

4826

European-Finnish (FIN)

AF:

0.312

AC:

3301

AN:

10586

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.361

AC:

24491

AN:

67936

Other (OTH)

AF:

0.346

AC:

730

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1827

3653

5480

7306

9133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

544

1088

1632

2176

2720

<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:

0.365

Hom.:

26930

Bravo

AF:

0.364

TwinsUK

AF:

0.389

AC:

1444

ALSPAC

AF:

0.409

AC:

1576

ESP6500AA

AF:

0.378

AC:

1664

ESP6500EA

AF:

0.369

AC:

3177

ExAC

AF:

0.357

AC:

43354

Asia WGS

AF:

0.335

AC:

1166

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.6

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.018

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.043

MetaRNN

Benign

0.00092

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.040

PhyloP100

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

0.33

REVEL

Benign

0.21

Sift

Benign

0.40

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.0070

MPC

0.19

ClinPred

0.00030

GERP RS

2.4

Varity_R

0.086

gMVP

0.53

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over