NM_004557.4:c.5427A>G

Variant names:

• chr6-32196022-T-C
• rs8192579
• NM_004557.4:c.5427A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_004557.4(NOTCH4):​c.5427A>G​(p.Gln1809Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,598,326 control chromosomes in the GnomAD database, including 2,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.062 (343 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2542 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.123).
• BP6: Variant 6-32196022-T-C is Benign according to our data. Variant chr6-32196022-T-C is described in ClinVar as Benign. ClinVar VariationId is 1290716.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.165 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0916 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.5427A>G	p.Gln1809Gln	synonymous	Exon 30 of 30	NP_004548.3
	NOTCH4	NR_134949.2		n.5135A>G		non_coding_transcript_exon	Exon 30 of 30
	NOTCH4	NR_134950.2		n.5033A>G		non_coding_transcript_exon	Exon 29 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.5427A>G	p.Gln1809Gln	synonymous	Exon 30 of 30	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000883244.1		c.5418A>G	p.Gln1806Gln	synonymous	Exon 30 of 30	ENSP00000553303.1
	NOTCH4	ENST00000883245.1		c.5295A>G	p.Gln1765Gln	synonymous	Exon 29 of 29	ENSP00000553304.1

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 9371 AN: 152118 Hom.: 345 Cov.: 33

Gnomad AFR AF: 0.0814

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0506

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0566

Gnomad OTH AF: 0.0669

GnomAD2 exomes AF: 0.0531 AC: 11572 AN: 217950 AF XY: 0.0569

Gnomad AFR exome AF: 0.0810

Gnomad AMR exome AF: 0.0313

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.0365

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0516

Gnomad OTH exome AF: 0.0557

GnomAD4 exome AF: 0.0562 AC: 81251 AN: 1446090 Hom.: 2542 Cov.: 32 AF XY: 0.0571 AC XY: 41073 AN XY: 719706

African (AFR) AF: 0.0893 AC: 2983 AN: 33398

American (AMR) AF: 0.0346 AC: 1534 AN: 44388

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 1291 AN: 26034

East Asian (EAS) AF: 0.0539 AC: 2131 AN: 39554

South Asian (SAS) AF: 0.0934 AC: 8013 AN: 85770

European-Finnish (FIN) AF: 0.0212 AC: 858 AN: 40436

Middle Eastern (MID) AF: 0.0708 AC: 408 AN: 5764

European-Non Finnish (NFE) AF: 0.0544 AC: 60470 AN: 1110648

Other (OTH) AF: 0.0593 AC: 3563 AN: 60098

GnomAD4 genome AF: 0.0615 AC: 9369 AN: 152236 Hom.: 343 Cov.: 33 AF XY: 0.0604 AC XY: 4499 AN XY: 74436

African (AFR) AF: 0.0812 AC: 3375 AN: 41548

American (AMR) AF: 0.0505 AC: 773 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 158 AN: 3466

East Asian (EAS) AF: 0.0468 AC: 242 AN: 5172

South Asian (SAS) AF: 0.0989 AC: 477 AN: 4822

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10622

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0566 AC: 3848 AN: 67986

Other (OTH) AF: 0.0662 AC: 140 AN: 2116

Alfa AF: 0.0509 Hom.: 110

Bravo AF: 0.0648

Asia WGS AF: 0.0690 AC: 240 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	-0.61
CADD	Benign	9.1
DANN	Benign	0.85
PhyloP100		-0.17
PromoterAI		-0.19	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs8192579; hg19: chr6-32163799; COSMIC: COSV66678923; COSMIC: COSV66678923;