6-32195497-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004557.4(NOTCH4):c.5952C>A(p.Asp1984Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1984D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.713

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]

GPSM3 (HGNC:13945): (G protein signaling modulator 3) Predicted to enable GTPase regulator activity. Predicted to be involved in positive regulation of inflammatory response. Predicted to act upstream of or within positive regulation of cytokine production involved in inflammatory response and positive regulation of leukocyte chemotaxis. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07781103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.5952C>A	p.Asp1984Glu	missense_variant	30/30	ENST00000375023.3
GPSM3	NM_022107.3	c.-347C>A		5_prime_UTR_variant	1/8
NOTCH4	NR_134949.2	n.5660C>A		non_coding_transcript_exon_variant	30/30
NOTCH4	NR_134950.2	n.5558C>A		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.5952C>A	p.Asp1984Glu	missense_variant	30/30	1	NM_004557.4	P1
GPSM3	ENST00000375043.3	c.-347C>A		5_prime_UTR_variant	1/8	1		P1
NOTCH4	ENST00000474612.1	n.4613C>A		non_coding_transcript_exon_variant	10/10	5
NOTCH4	ENST00000491215.1	n.978C>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460580 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.23
Dann	Benign	0.65
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.54	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.14
Sift	Benign	0.10	T
Sift4G	Benign	0.31	T
Polyphen		0.010	B
Vest4		0.048
MutPred		0.10		Gain of solvent accessibility (P = 0.005);
MVP		0.57
MPC		0.58
ClinPred		0.032	T
GERP RS		-4.2
Varity_R		0.035
gMVP		0.035

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: rs8192583; hg19: chr6-32163274;