chr6-32205216-C-T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_004557.4(NOTCH4):c.2866-827G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.106 (AC=16,065) in the gnomAD database across 151,500 control chromosomes, including 982 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.131. 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: 𝑓 0.11 (982 hom., cov: 31)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.703
• Publications: 124 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1311 — exceeds 5%% threshold (BA1 applied)

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>A	intron	Intron 18 of 29	Prot: NP_004548.3
	NOTCH4 NR_134949.2		n.3107-827G>A	intron	Intron 19 of 29	Prot:
	NOTCH4 NR_134950.2		n.3005-827G>A	intron	Intron 18 of 28	Prot:

NOTCH4 NM_004557.4

MANE Select

HGVSc / HGVSpc.2866-827G>A

Exon rankIntron 18 of 29

intron

Prot: NP_004548.3

NOTCH4 NR_134949.2

HGVSc / HGVSpn.3107-827G>A

Exon rankIntron 19 of 29

intron

Prot:

NOTCH4 NR_134950.2

HGVSc / HGVSpn.3005-827G>A

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>A	intron	Intron 18 of 29	Prot: ENSP00000364163.3 UniProt:
	NOTCH4 ENST00000883244.1		c.2866-827G>A	intron	Intron 18 of 29	Prot: ENSP00000553303.1 UniProt:
	NOTCH4 ENST00000883245.1		c.2743-827G>A	intron	Intron 17 of 28	Prot: ENSP00000553304.1 UniProt:

NOTCH4 ENST00000375023.3

TSL:1MANE Select

HGVSc / HGVSpc.2866-827G>A

Exon rankIntron 18 of 29

intron

Prot: ENSP00000364163.3UniProt: Q99466-1

NOTCH4 ENST00000883244.1

HGVSc / HGVSpc.2866-827G>A

Exon rankIntron 18 of 29

intron

Prot: ENSP00000553303.1UniProt: A0ACI8RKS9

NOTCH4 ENST00000883245.1

HGVSc / HGVSpc.2743-827G>A

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.106	AC:16068	Hom:982	AN:151386	Cov:31
GnomAD4 genome	AF: 0.106	AC:16065	Hom:982	AN:151500	Cov:31
TOPMed (Bravo)	AF: 0.101	AC:26818	Hom:1507	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.129	AC:68948	Hom:5056	AN:533816	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0722	AC:169	Hom:6	AN:2342	Cov:
GenomeAsia100K	AF: 0.0550	AC:193	Hom:	AN:3466	Cov:
Korea4K (4,157 Koreans)	AF: 0.0590	AC:426	Hom:	AN:7200	Cov:
Qatari Genome	AF: 0.0398	AC:7	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00408	AC:425	Hom:28	AN:104212	Cov:
Turkish Variome	AF: 0.0505	AC:78	Hom:1	AN:1546	Cov:
UK10K	AF: 0.147	AC:1109	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0286	AC:256	Hom:15	AN:8960	Cov:

Showing 12 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	Benign	7.6
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.2
DANN	Benign	0.49
GPN-Star LLR	N/A	0.24
GPN-Star score	N/A	-0.24
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.70

Showing 8 of 8 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