6-32198607-C-G

Variant names:

• chr6-32198607-C-G
• rs8192575
• NM_004557.4:c.4617+42G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004557.4(NOTCH4):​c.4617+42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 1,610,484 control chromosomes in the GnomAD database, including 4,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (339 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4294 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22
• Publications: 28 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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-32198607-C-G is Benign according to our data. Variant chr6-32198607-C-G is described in ClinVar as Benign. ClinVar VariationId is 1232677.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	NM_004557.4	MANE Select	c.4617+42G>C		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.4326-48G>C		intron	N/A
	NOTCH4	NR_134950.2		n.4224-48G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.4617+42G>C		intron	N/A	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000883244.1		c.4609-48G>C		intron	N/A	ENSP00000553303.1
	NOTCH4	ENST00000883245.1		c.4486-48G>C		intron	N/A	ENSP00000553304.1

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8560 AN: 152024 Hom.: 336 Cov.: 32

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0574

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0703

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0656

GnomAD2 exomes AF: 0.0697 AC: 17014 AN: 244020 AF XY: 0.0676

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.0716

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0586

Gnomad OTH exome AF: 0.0746

GnomAD4 exome AF: 0.0702 AC: 102427 AN: 1458342 Hom.: 4294 Cov.: 35 AF XY: 0.0696 AC XY: 50477 AN XY: 725282

African (AFR) AF: 0.0358 AC: 1199 AN: 33446

American (AMR) AF: 0.0695 AC: 3092 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3921 AN: 25938

East Asian (EAS) AF: 0.209 AC: 8270 AN: 39664

South Asian (SAS) AF: 0.0613 AC: 5267 AN: 85930

European-Finnish (FIN) AF: 0.0292 AC: 1528 AN: 52244

Middle Eastern (MID) AF: 0.0711 AC: 409 AN: 5756

European-Non Finnish (NFE) AF: 0.0668 AC: 74142 AN: 1110622

Other (OTH) AF: 0.0763 AC: 4599 AN: 60268

GnomAD4 genome AF: 0.0563 AC: 8572 AN: 152142 Hom.: 339 Cov.: 32 AF XY: 0.0557 AC XY: 4147 AN XY: 74390

African (AFR) AF: 0.0365 AC: 1514 AN: 41510

American (AMR) AF: 0.0579 AC: 884 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 515 AN: 3472

East Asian (EAS) AF: 0.197 AC: 1015 AN: 5156

South Asian (SAS) AF: 0.0702 AC: 338 AN: 4818

European-Finnish (FIN) AF: 0.0275 AC: 292 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0561 AC: 3817 AN: 67984

Other (OTH) AF: 0.0678 AC: 143 AN: 2110

Alfa AF: 0.0702 Hom.: 293

Bravo AF: 0.0597

Asia WGS AF: 0.0950 AC: 329 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.57
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: 42

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

Other links and lift over

dbSNP: rs8192575; hg19: chr6-32166384; COSMIC: COSV66678967; COSMIC: COSV66678967;