6-32221166-G-T

Variant names:

• chr6-32221166-G-T
• rs2071282
• NM_004557.4:c.611C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004557.4(NOTCH4):​c.611C>A​(p.Pro204His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P204L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.611C>A	p.Pro204His	missense_variant	Exon 4 of 30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.750C>A		non_coding_transcript_exon_variant	Exon 4 of 30
NOTCH4	NR_134950.2	n.750C>A		non_coding_transcript_exon_variant	Exon 4 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.611C>A	p.Pro204His	missense_variant	Exon 4 of 30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.740C>A		non_coding_transcript_exon_variant	Exon 4 of 11	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.21	T
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.9	M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.49
Sift	Benign	0.10	T
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.32
MutPred		0.41		Loss of phosphorylation at T209 (P = 0.1441);
MVP		0.95
MPC		0.73
ClinPred		0.92	D
GERP RS		2.4
Varity_R		0.27
gMVP		0.51

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;