rs422951

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_004557.4(NOTCH4):c.958A>G(p.Thr320Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,226 control chromosomes in the GnomAD database, including 152,441 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 0.40 ( 12552 hom., cov: 32)

Exomes 𝑓: 0.43 ( 139889 hom. )

Consequence

NOTCH4
NM_004557.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.154

Publications

97 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=5.7498703E-5).

BP6

Variant 6-32220606-T-C is Benign according to our data. Variant chr6-32220606-T-C is described in ClinVar as Benign. ClinVar VariationId is 1297197.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.452 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.958A>G	p.Thr320Ala	missense	Exon 6 of 30	NP_004548.3
NOTCH4	NR_134949.2		n.1097A>G		non_coding_transcript_exon	Exon 6 of 30
NOTCH4	NR_134950.2		n.1097A>G		non_coding_transcript_exon	Exon 6 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.958A>G	p.Thr320Ala	missense	Exon 6 of 30	ENSP00000364163.3	Q99466-1
NOTCH4	ENST00000473562.1	TSL:1	n.1087A>G		non_coding_transcript_exon	Exon 6 of 11
NOTCH4	ENST00000883244.1		c.958A>G	p.Thr320Ala	missense	Exon 6 of 30	ENSP00000553303.1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60127

AN:

151664

Hom.:

12551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.457

Gnomad AMR

AF:

0.376

Gnomad ASJ

AF:

0.584

Gnomad EAS

AF:

0.194

Gnomad SAS

AF:

0.412

Gnomad FIN

AF:

0.432

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.456

Gnomad OTH

AF:

0.401

GnomAD2 exomes

AF:

0.401

AC:

99350

AN:

248050

AF XY:

0.411

show subpopulations

Gnomad AFR exome

AF:

0.302

Gnomad AMR exome

AF:

0.307

Gnomad ASJ exome

AF:

0.587

Gnomad EAS exome

AF:

0.168

Gnomad FIN exome

AF:

0.427

Gnomad NFE exome

AF:

0.456

Gnomad OTH exome

AF:

0.431

GnomAD4 exome

AF:

0.432

AC:

631140

AN:

1461444

Hom.:

139889

Cov.:

AF XY:

0.433

AC XY:

315121

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.299

AC:

10023

AN:

33480

American (AMR)

AF:

0.313

AC:

14001

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.583

AC:

15236

AN:

26130

East Asian (EAS)

AF:

0.210

AC:

8337

AN:

39698

South Asian (SAS)

AF:

0.406

AC:

35032

AN:

86256

European-Finnish (FIN)

AF:

0.423

AC:

22526

AN:

53312

Middle Eastern (MID)

AF:

0.441

AC:

2541

AN:

5764

European-Non Finnish (NFE)

AF:

0.448

AC:

497515

AN:

1111708

Other (OTH)

AF:

0.429

AC:

25929

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

21844

43689

65533

87378

109222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14722

29444

44166

58888

73610

<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:

0.396

AC:

60133

AN:

151782

Hom.:

12552

Cov.:

AF XY:

0.394

AC XY:

29213

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.301

AC:

12469

AN:

41366

American (AMR)

AF:

0.375

AC:

5724

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

2025

AN:

3468

East Asian (EAS)

AF:

0.194

AC:

992

AN:

5116

South Asian (SAS)

AF:

0.411

AC:

1971

AN:

4796

European-Finnish (FIN)

AF:

0.432

AC:

4571

AN:

10572

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.456

AC:

30980

AN:

67890

Other (OTH)

AF:

0.403

AC:

845

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1829

3657

5486

7314

9143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.436

Hom.:

47930

Bravo

AF:

0.386

TwinsUK

AF:

0.434

AC:

1611

ALSPAC

AF:

0.433

AC:

1669

ESP6500AA

AF:

0.312

AC:

942

ESP6500EA

AF:

0.450

AC:

2436

ExAC

AF:

0.400

AC:

48465

Asia WGS

AF:

0.372

AC:

1301

AN:

3478

EpiCase

AF:

0.475

EpiControl

AF:

0.477

ClinVar

ClinVar submissions

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

0.060

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.042

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.13

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.046

MetaRNN

Benign

0.000058

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.57

PhyloP100

-0.15

PrimateAI

Benign

0.30

PROVEAN

Benign

0.42

REVEL

Benign

0.28

Sift

Benign

0.55

Sift4G

Benign

0.72

Polyphen

0.0

Vest4

0.020

MPC

0.18

ClinPred

0.0039

GERP RS

-5.0

Varity_R

0.061

gMVP

0.38

Mutation Taster

=96/4

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