rs2229968

Variant names:

• chr9-136504680-C-T
• rs2229968
• NM_017617.5:c.5011G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017617.5(NOTCH1):​c.5011G>A​(p.Val1671Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,516,392 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: NOTCH1 NM_017617.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -0.129
• Publications: 14 publications found

Genes affected

NOTCH1 (HGNC:7881): (notch receptor 1) 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 plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]

NOTCH1 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• Adams-Oliver syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• NOTCH1-related AOS spectrum disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• aortic valve disease 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leukodystrophy

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial bicuspid aortic valve

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041054487).
• BP6: Variant 9-136504680-C-T is Benign according to our data. Variant chr9-136504680-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00835 (1272/152322) while in subpopulation AFR AF = 0.0277 (1153/41560). AF 95% confidence interval is 0.0264. There are 12 homozygotes in GnomAd4. There are 603 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1272 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017617.5. 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
	NOTCH1	NM_017617.5	MANE Select	c.5011G>A	p.Val1671Ile	missense	Exon 26 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.5011G>A	p.Val1671Ile	missense	Exon 26 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.4900G>A	p.Val1634Ile	missense	Exon 26 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.4897G>A	p.Val1633Ile	missense	Exon 25 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1264 AN: 152204 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00245 AC: 306 AN: 125056 AF XY: 0.00216

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00262

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000160

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.00106 AC: 1444 AN: 1364070 Hom.: 8 Cov.: 33 AF XY: 0.000944 AC XY: 631 AN XY: 668660

African (AFR) AF: 0.0279 AC: 859 AN: 30778

American (AMR) AF: 0.00341 AC: 113 AN: 33094

Ashkenazi Jewish (ASJ) AF: 0.00209 AC: 48 AN: 23016

East Asian (EAS) AF: 0.00 AC: 0 AN: 35278

South Asian (SAS) AF: 0.000468 AC: 35 AN: 74734

European-Finnish (FIN) AF: 0.0000877 AC: 4 AN: 45624

Middle Eastern (MID) AF: 0.00316 AC: 13 AN: 4116

European-Non Finnish (NFE) AF: 0.000232 AC: 246 AN: 1061134

Other (OTH) AF: 0.00224 AC: 126 AN: 56296

GnomAD4 genome AF: 0.00835 AC: 1272 AN: 152322 Hom.: 12 Cov.: 33 AF XY: 0.00810 AC XY: 603 AN XY: 74478

African (AFR) AF: 0.0277 AC: 1153 AN: 41560

American (AMR) AF: 0.00464 AC: 71 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68018

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00265 Hom.: 5

Bravo AF: 0.00971

ESP6500AA AF: 0.0179 AC: 56

ESP6500EA AF: 0.000296 AC: 2

ExAC AF: 0.000989 AC: 74

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	3	not provided (3)
-	-	2	Adams-Oliver syndrome 5 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Aortic valve disease 1 (1)
-	-	1	Aortic valve disease 1;C4014970:Adams-Oliver syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.4
DANN	Benign	0.93
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.13
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.022
Sift	Benign	0.51	T
Sift4G	Benign	0.44	T
Polyphen		0.0060	B
Vest4		0.12
MVP		0.30
MPC		0.65
ClinPred		0.0021	T
GERP RS		-1.1
Varity_R		0.063
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs2229968; hg19: chr9-139399132; COSMIC: COSV53038538;