rs1044507

Variant names:

• chr6-32195764-A-C
• rs1044507
• NM_004557.4:c.5685T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-32195764-A-C
• chr6-32195764-A-T

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.5685T>G​(p.Ser1895Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,610,698 control chromosomes in the GnomAD database, including 918 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (79 hom., cov: 33)
  • Exomes 𝑓: 0.027 (839 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.43
• Publications: 8 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]

GPSM3 (HGNC:13945): (G protein signaling modulator 3) Predicted to enable GTPase regulator activity. Predicted to be involved in positive regulation of inflammatory response. Predicted to act upstream of or within positive regulation of cytokine production involved in inflammatory response and positive regulation of leukocyte chemotaxis. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-32195764-A-C is Benign according to our data. Variant chr6-32195764-A-C is described in ClinVar as Benign. ClinVar VariationId is 1241905.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0863 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.5685T>G	p.Ser1895Ser	synonymous	Exon 30 of 30	NP_004548.3
	NOTCH4	NR_134949.2		n.5393T>G		non_coding_transcript_exon	Exon 30 of 30
	NOTCH4	NR_134950.2		n.5291T>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.5685T>G	p.Ser1895Ser	synonymous	Exon 30 of 30	ENSP00000364163.3	Q99466-1
	NOTCH4	ENST00000883244.1		c.5676T>G	p.Ser1892Ser	synonymous	Exon 30 of 30	ENSP00000553303.1
	NOTCH4	ENST00000883245.1		c.5553T>G	p.Ser1851Ser	synonymous	Exon 29 of 29	ENSP00000553304.1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3865 AN: 152134 Hom.: 79 Cov.: 33

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.0282

Gnomad SAS AF: 0.0940

Gnomad FIN AF: 0.0326

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0264

GnomAD2 exomes AF: 0.0303 AC: 7246 AN: 238836 AF XY: 0.0331

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0411

Gnomad EAS exome AF: 0.0316

Gnomad FIN exome AF: 0.0315

Gnomad NFE exome AF: 0.0246

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0268 AC: 39040 AN: 1458446 Hom.: 839 Cov.: 32 AF XY: 0.0284 AC XY: 20590 AN XY: 725626

African (AFR) AF: 0.0185 AC: 619 AN: 33478

American (AMR) AF: 0.0138 AC: 616 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 1036 AN: 26116

East Asian (EAS) AF: 0.0196 AC: 780 AN: 39700

South Asian (SAS) AF: 0.0748 AC: 6453 AN: 86230

European-Finnish (FIN) AF: 0.0294 AC: 1482 AN: 50384

Middle Eastern (MID) AF: 0.0248 AC: 143 AN: 5764

European-Non Finnish (NFE) AF: 0.0236 AC: 26218 AN: 1111762

Other (OTH) AF: 0.0281 AC: 1693 AN: 60316

GnomAD4 genome AF: 0.0253 AC: 3858 AN: 152252 Hom.: 79 Cov.: 33 AF XY: 0.0268 AC XY: 1994 AN XY: 74434

African (AFR) AF: 0.0166 AC: 690 AN: 41550

American (AMR) AF: 0.0130 AC: 199 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3468

East Asian (EAS) AF: 0.0285 AC: 147 AN: 5164

South Asian (SAS) AF: 0.0935 AC: 451 AN: 4826

European-Finnish (FIN) AF: 0.0326 AC: 346 AN: 10610

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.0268 AC: 1822 AN: 68016

Other (OTH) AF: 0.0261 AC: 55 AN: 2108

Alfa AF: 0.0274 Hom.: 46

Bravo AF: 0.0237

Asia WGS AF: 0.0420 AC: 146 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0280

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	-0.82
CADD	Benign	0.54
DANN	Benign	0.69
PhyloP100		-4.4
PromoterAI		0.062	Neutral
Mutation Taster		=100/0	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: rs1044507; hg19: chr6-32163541; COSMIC: COSV66678966;