rs2071282

Positions:

• chr6-32221166-G-A
• chr6-32221166-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004557.4(NOTCH4):​c.611C>T​(p.Pro204Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,613,114 control chromosomes in the GnomAD database, including 153 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0023 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (138 hom.)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.697

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006144017).
• BP6: Variant 6-32221166-G-A is Benign according to our data. Variant chr6-32221166-G-A is described in ClinVar as [Benign]. Clinvar id is 707916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.611C>T	p.Pro204Leu	missense_variant	4/30	ENST00000375023.3
NOTCH4	NR_134949.2	n.750C>T		non_coding_transcript_exon_variant	4/30
NOTCH4	NR_134950.2	n.750C>T		non_coding_transcript_exon_variant	4/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.611C>T	p.Pro204Leu	missense_variant	4/30	1	NM_004557.4	P1
NOTCH4	ENST00000473562.1	n.740C>T		non_coding_transcript_exon_variant	4/11	1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152236 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0604

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00475 AC: 1164 AN: 245238 Hom.: 23 AF XY: 0.00462 AC XY: 618 AN XY: 133754

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0553

Gnomad SAS exome AF: 0.00471

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00254 AC: 3717 AN: 1460760 Hom.: 138 Cov.: 45 AF XY: 0.00261 AC XY: 1898 AN XY: 726698

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0804

Gnomad4 SAS exome AF: 0.00421

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152354 Hom.: 15 Cov.: 33 AF XY: 0.00277 AC XY: 206 AN XY: 74502

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0607

Gnomad4 SAS AF: 0.00517

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00182 Hom.: 11

Bravo AF: 0.00209

ESP6500AA AF: 0.000331 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00500 AC: 592

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.18
Sift	Benign	0.099	T
Sift4G	Benign	0.50	T
Polyphen		0.081	B
Vest4		0.14
MVP		0.91
MPC		0.19
ClinPred		0.019	T
GERP RS		2.4
Varity_R		0.075
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs2071282; hg19: chr6-32188943; COSMIC: COSV66680876;