6-32200994-G-T

Variant names:

• chr6-32200994-G-T
• rs3134942
• NM_004557.4:c.4152C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004557.4(NOTCH4):​c.4152C>A​(p.Val1384Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,572,234 control chromosomes in the GnomAD database, including 14,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. V1384V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (962 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13489 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.228
• Publications: 72 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 6-32200994-G-T is Benign according to our data. Variant chr6-32200994-G-T is described in ClinVar as Benign. ClinVar VariationId is 1259043.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.228 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 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.4152C>A	p.Val1384Val	synonymous	Exon 23 of 30	NP_004548.3
	NOTCH4	NR_134949.2		n.3869C>A		non_coding_transcript_exon	Exon 23 of 30
	NOTCH4	NR_134950.2		n.3767C>A		non_coding_transcript_exon	Exon 22 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.4152C>A	p.Val1384Val	synonymous	Exon 23 of 30	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000883244.1		c.4152C>A	p.Val1384Val	synonymous	Exon 23 of 30	ENSP00000553303.1
	NOTCH4	ENST00000883245.1		c.4029C>A	p.Val1343Val	synonymous	Exon 22 of 29	ENSP00000553304.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16028 AN: 151982 Hom.: 962 Cov.: 32

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.0950

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.0872

GnomAD2 exomes AF: 0.0966 AC: 20445 AN: 211736 AF XY: 0.0979

Gnomad AFR exome AF: 0.0947

Gnomad AMR exome AF: 0.0417

Gnomad ASJ exome AF: 0.0877

Gnomad EAS exome AF: 0.0326

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.0998

GnomAD4 exome AF: 0.130 AC: 184567 AN: 1420132 Hom.: 13489 Cov.: 33 AF XY: 0.128 AC XY: 89933 AN XY: 702066

African (AFR) AF: 0.0854 AC: 2784 AN: 32586

American (AMR) AF: 0.0436 AC: 1764 AN: 40480

Ashkenazi Jewish (ASJ) AF: 0.0837 AC: 1911 AN: 22836

East Asian (EAS) AF: 0.0198 AC: 779 AN: 39362

South Asian (SAS) AF: 0.0771 AC: 6093 AN: 79046

European-Finnish (FIN) AF: 0.115 AC: 5796 AN: 50610

Middle Eastern (MID) AF: 0.0437 AC: 243 AN: 5566

European-Non Finnish (NFE) AF: 0.145 AC: 158205 AN: 1090994

Other (OTH) AF: 0.119 AC: 6992 AN: 58652

GnomAD4 genome AF: 0.105 AC: 16025 AN: 152102 Hom.: 962 Cov.: 32 AF XY: 0.102 AC XY: 7619 AN XY: 74376

African (AFR) AF: 0.0911 AC: 3777 AN: 41482

American (AMR) AF: 0.0542 AC: 829 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 266 AN: 3470

East Asian (EAS) AF: 0.0284 AC: 147 AN: 5178

South Asian (SAS) AF: 0.0943 AC: 454 AN: 4816

European-Finnish (FIN) AF: 0.117 AC: 1236 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9052 AN: 67938

Other (OTH) AF: 0.0863 AC: 182 AN: 2110

Alfa AF: 0.119 Hom.: 3663

Bravo AF: 0.101

Asia WGS AF: 0.0510 AC: 177 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	-0.63
CADD	Benign	1.7
DANN	Benign	0.59
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3134942; hg19: chr6-32168771; COSMIC: COSV66678970; COSMIC: COSV66678970;