6-32223830-C-T

Variant names:

• chr6-32223830-C-T
• rs8192565
• NM_004557.4:c.73+26G>A

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.73+26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,587,900 control chromosomes in the GnomAD database, including 7,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.086 (684 hom., cov: 30)
  • Exomes 𝑓: 0.088 (6419 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.356
• Publications: 15 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 6-32223830-C-T is Benign according to our data. Variant chr6-32223830-C-T is described in ClinVar as Benign. ClinVar VariationId is 1275095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	NM_004557.4	MANE Select	c.73+26G>A		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.212+26G>A		intron	N/A
	NOTCH4	NR_134950.2		n.212+26G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.73+26G>A		intron	N/A	ENSP00000364163.3
	NOTCH4	ENST00000473562.1	TSL:1	n.202+26G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0858 AC: 13033 AN: 151866 Hom.: 679 Cov.: 30

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0953

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0984

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0941

Gnomad OTH AF: 0.0929

GnomAD2 exomes AF: 0.0781 AC: 17784 AN: 227736 AF XY: 0.0806

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.0755

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.0591

Gnomad FIN exome AF: 0.0885

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0884 AC: 126976 AN: 1435916 Hom.: 6419 Cov.: 30 AF XY: 0.0895 AC XY: 63876 AN XY: 713836

African (AFR) AF: 0.0326 AC: 1066 AN: 32708

American (AMR) AF: 0.0825 AC: 3425 AN: 41500

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4383 AN: 24366

East Asian (EAS) AF: 0.118 AC: 4574 AN: 38600

South Asian (SAS) AF: 0.105 AC: 8683 AN: 83006

European-Finnish (FIN) AF: 0.0962 AC: 4792 AN: 49798

Middle Eastern (MID) AF: 0.120 AC: 677 AN: 5640

European-Non Finnish (NFE) AF: 0.0854 AC: 94069 AN: 1101066

Other (OTH) AF: 0.0896 AC: 5307 AN: 59232

GnomAD4 genome AF: 0.0858 AC: 13039 AN: 151984 Hom.: 684 Cov.: 30 AF XY: 0.0882 AC XY: 6548 AN XY: 74258

African (AFR) AF: 0.0417 AC: 1730 AN: 41472

American (AMR) AF: 0.113 AC: 1722 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 749 AN: 3470

East Asian (EAS) AF: 0.0946 AC: 486 AN: 5138

South Asian (SAS) AF: 0.118 AC: 568 AN: 4800

European-Finnish (FIN) AF: 0.0984 AC: 1041 AN: 10580

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0940 AC: 6389 AN: 67934

Other (OTH) AF: 0.0995 AC: 210 AN: 2110

Alfa AF: 0.0893 Hom.: 1055

Bravo AF: 0.0823

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

ClinVar submissions as Germline

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	2.0
DANN	Benign	0.42
PhyloP100		-0.36
PromoterAI		-0.12	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs8192565; hg19: chr6-32191607; COSMIC: COSV66678825;