rs35980907

Variant names:

• chr9-136503225-C-A
• rs35980907
• NM_017617.5:c.5124G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136503225-C-A
• chr9-136503225-C-T
• chr9-136503225-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017617.5(NOTCH1):​c.5124G>T​(p.Ser1708Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,612,792 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1708S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (44 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -0.851
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-136503225-C-A is Benign according to our data. Variant chr9-136503225-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.851 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00512 (780/152302) while in subpopulation NFE AF = 0.0087 (592/68026). AF 95% confidence interval is 0.00812. There are 2 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 780 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.5124G>T	p.Ser1708Ser	synonymous	Exon 27 of 34	NP_060087.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.5124G>T	p.Ser1708Ser	synonymous	Exon 27 of 34	ENSP00000498587.1	P46531
	NOTCH1	ENST00000927794.1		c.5013G>T	p.Ser1671Ser	synonymous	Exon 27 of 34	ENSP00000597853.1
	NOTCH1	ENST00000680133.1		c.5010G>T	p.Ser1670Ser	synonymous	Exon 26 of 33	ENSP00000505319.1	A0A7P0T8U6

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 780 AN: 152184 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00460 AC: 1139 AN: 247722 AF XY: 0.00476

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00300

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00403

Gnomad NFE exome AF: 0.00774

Gnomad OTH exome AF: 0.00699

GnomAD4 exome AF: 0.00689 AC: 10067 AN: 1460490 Hom.: 44 Cov.: 31 AF XY: 0.00666 AC XY: 4839 AN XY: 726552

African (AFR) AF: 0.00131 AC: 44 AN: 33474

American (AMR) AF: 0.00275 AC: 123 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86252

European-Finnish (FIN) AF: 0.00368 AC: 192 AN: 52146

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00834 AC: 9270 AN: 1111940

Other (OTH) AF: 0.00508 AC: 307 AN: 60382

GnomAD4 genome AF: 0.00512 AC: 780 AN: 152302 Hom.: 2 Cov.: 33 AF XY: 0.00471 AC XY: 351 AN XY: 74474

African (AFR) AF: 0.00152 AC: 63 AN: 41574

American (AMR) AF: 0.00386 AC: 59 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00870 AC: 592 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00566 Hom.: 1

Bravo AF: 0.00468

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00788

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	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)
-	-	1	Connective tissue disorder (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.40
DANN	Benign	0.86
PhyloP100		-0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs35980907; hg19: chr9-139397677; COSMIC: COSV53054324;