NM_017617.5:c.6555C>T

Variant names:

• chr9-136497184-G-A
• rs2229974
• NM_017617.5:c.6555C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017617.5(NOTCH1):​c.6555C>T​(p.Asp2185Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,612,574 control chromosomes in the GnomAD database, including 272,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27352 hom., cov: 34)
  • Exomes 𝑓: 0.57 (244678 hom.)
• Consequence: NOTCH1 NM_017617.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.259
• Publications: 46 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: Illumina, Orphanet
• Adams-Oliver syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• aortic valve disease 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
• 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
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 9-136497184-G-A is Benign according to our data. Variant chr9-136497184-G-A is described in ClinVar as Benign. ClinVar VariationId is 286141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.259 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	NM_017617.5	MANE Select	c.6555C>T	p.Asp2185Asp	synonymous	Exon 34 of 34	NP_060087.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH1	ENST00000651671.1	MANE Select	c.6555C>T	p.Asp2185Asp	synonymous	Exon 34 of 34	ENSP00000498587.1
	NOTCH1	ENST00000680133.1		c.6441C>T	p.Asp2147Asp	synonymous	Exon 33 of 33	ENSP00000505319.1
	NOTCH1	ENST00000680668.1		c.6441C>T	p.Asp2147Asp	synonymous	Exon 33 of 33	ENSP00000506336.1

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90363 AN: 152036 Hom.: 27331 Cov.: 34

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.939

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.579

GnomAD2 exomes AF: 0.622 AC: 154009 AN: 247630 AF XY: 0.619

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.539

Gnomad EAS exome AF: 0.950

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.551

Gnomad OTH exome AF: 0.587

GnomAD4 exome AF: 0.573 AC: 837301 AN: 1460420 Hom.: 244678 Cov.: 87 AF XY: 0.576 AC XY: 418836 AN XY: 726538

African (AFR) AF: 0.621 AC: 20772 AN: 33476

American (AMR) AF: 0.714 AC: 31933 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 13885 AN: 26132

East Asian (EAS) AF: 0.909 AC: 36099 AN: 39694

South Asian (SAS) AF: 0.680 AC: 58654 AN: 86256

European-Finnish (FIN) AF: 0.520 AC: 27104 AN: 52076

Middle Eastern (MID) AF: 0.553 AC: 3190 AN: 5766

European-Non Finnish (NFE) AF: 0.549 AC: 610124 AN: 1111934

Other (OTH) AF: 0.589 AC: 35540 AN: 60370

GnomAD4 genome AF: 0.594 AC: 90415 AN: 152154 Hom.: 27352 Cov.: 34 AF XY: 0.600 AC XY: 44643 AN XY: 74378

African (AFR) AF: 0.620 AC: 25754 AN: 41506

American (AMR) AF: 0.649 AC: 9928 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1846 AN: 3470

East Asian (EAS) AF: 0.939 AC: 4862 AN: 5176

South Asian (SAS) AF: 0.686 AC: 3310 AN: 4828

European-Finnish (FIN) AF: 0.512 AC: 5430 AN: 10610

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37525 AN: 67952

Other (OTH) AF: 0.581 AC: 1225 AN: 2110

Alfa AF: 0.568 Hom.: 65664

Bravo AF: 0.607

Asia WGS AF: 0.786 AC: 2732 AN: 3478

EpiCase AF: 0.566

EpiControl AF: 0.566

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.94
DANN	Benign	0.84
PhyloP100		-0.26
Mutation Taster		=97/3	polymorphism (auto)

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: rs2229974; hg19: chr9-139391636; COSMIC: COSV53025449;