NM_004557.4:c.2866-827G>C

Variant names:

• chr6-32205216-C-G
• rs3131296
• NM_004557.4:c.2866-827G>C

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_004557.4(NOTCH4):c.2866-827G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The gene NOTCH4 is a tumor suppressor gene (CancerMine: 3 TSG, 4 oncogene, 3 driver citations). The gene NOTCH4 is a known oncogene (CancerMine: 3 TSG, 4 oncogene, 3 driver citations). The gene NOTCH4 is a cancer driver gene (CancerMine: 3 TSG, 4 oncogene, 3 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.703
• Publications: 0 publications found

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]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004557.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NOTCH4 NM_004557.4	MANE Select	c.2866-827G>C	intron	Intron 18 of 29	Prot: NP_004548.3
	NOTCH4 NR_134949.2		n.3107-827G>C	intron	Intron 19 of 29	Prot:
	NOTCH4 NR_134950.2		n.3005-827G>C	intron	Intron 18 of 28	Prot:

NOTCH4 NM_004557.4

MANE Select

HGVSc / HGVSpc.2866-827G>C

Exon rankIntron 18 of 29

intron

Prot: NP_004548.3

NOTCH4 NR_134949.2

HGVSc / HGVSpn.3107-827G>C

Exon rankIntron 19 of 29

intron

Prot:

NOTCH4 NR_134950.2

HGVSc / HGVSpn.3005-827G>C

Exon rankIntron 18 of 28

intron

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NOTCH4 ENST00000375023.3	TSL:1MANE Select	c.2866-827G>C	intron	Intron 18 of 29	Prot: ENSP00000364163.3 UniProt:
	NOTCH4 ENST00000883244.1		c.2866-827G>C	intron	Intron 18 of 29	Prot: ENSP00000553303.1 UniProt:
	NOTCH4 ENST00000883245.1		c.2743-827G>C	intron	Intron 17 of 28	Prot: ENSP00000553304.1 UniProt:

NOTCH4 ENST00000375023.3

TSL:1MANE Select

HGVSc / HGVSpc.2866-827G>C

Exon rankIntron 18 of 29

intron

Prot: ENSP00000364163.3UniProt: Q99466-1

NOTCH4 ENST00000883244.1

HGVSc / HGVSpc.2866-827G>C

Exon rankIntron 18 of 29

intron

Prot: ENSP00000553303.1UniProt: A0ACI8RKS9

NOTCH4 ENST00000883245.1

HGVSc / HGVSpc.2743-827G>C

Exon rankIntron 17 of 28

intron

Prot: ENSP00000553304.1UniProt: A0ACI8R327

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.8
DANN	Benign	0.44
GPN-Star LLR	N/A	0.48
GPN-Star score	N/A	-0.48
PhyloP100	Benign	0.70

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3131296;

hg19: chr6-32172993;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar