rs1044506

Variant names:

• chr6-32204288-T-G
• rs1044506
• NM_004557.4:c.2967A>C

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.2967A>C​(p.Gly989Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 1,613,012 control chromosomes in the GnomAD database, including 630,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.91 (63823 hom., cov: 32)
  • Exomes 𝑓: 0.88 (566987 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.337
• Publications: 50 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=-0.51).
• BP6: Variant 6-32204288-T-G is Benign according to our data. Variant chr6-32204288-T-G is described in ClinVar as Benign. ClinVar VariationId is 1277124.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.337 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.2967A>C	p.Gly989Gly	synonymous_variant	Exon 19 of 30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.3208A>C		non_coding_transcript_exon_variant	Exon 20 of 30
NOTCH4	NR_134950.2	n.3106A>C		non_coding_transcript_exon_variant	Exon 19 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.2967A>C	p.Gly989Gly	synonymous_variant	Exon 19 of 30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000474612.1	n.-118A>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.914 AC: 139054 AN: 152146 Hom.: 63760 Cov.: 32

Gnomad AFR AF: 0.973

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.935

Gnomad ASJ AF: 0.970

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.973

Gnomad FIN AF: 0.882

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.936

GnomAD2 exomes AF: 0.916 AC: 225770 AN: 246552 AF XY: 0.917

Gnomad AFR exome AF: 0.978

Gnomad AMR exome AF: 0.955

Gnomad ASJ exome AF: 0.974

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.871

Gnomad NFE exome AF: 0.869

Gnomad OTH exome AF: 0.903

GnomAD4 exome AF: 0.880 AC: 1284913 AN: 1460748 Hom.: 566987 Cov.: 70 AF XY: 0.883 AC XY: 641574 AN XY: 726694

African (AFR) AF: 0.978 AC: 32743 AN: 33480

American (AMR) AF: 0.953 AC: 42600 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 25386 AN: 26136

East Asian (EAS) AF: 0.999 AC: 39643 AN: 39700

South Asian (SAS) AF: 0.976 AC: 84158 AN: 86258

European-Finnish (FIN) AF: 0.866 AC: 45316 AN: 52312

Middle Eastern (MID) AF: 0.942 AC: 5436 AN: 5768

European-Non Finnish (NFE) AF: 0.860 AC: 955869 AN: 1111988

Other (OTH) AF: 0.890 AC: 53762 AN: 60384

GnomAD4 genome AF: 0.914 AC: 139175 AN: 152264 Hom.: 63823 Cov.: 32 AF XY: 0.916 AC XY: 68187 AN XY: 74460

African (AFR) AF: 0.973 AC: 40431 AN: 41548

American (AMR) AF: 0.935 AC: 14302 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.970 AC: 3369 AN: 3472

East Asian (EAS) AF: 0.995 AC: 5162 AN: 5186

South Asian (SAS) AF: 0.974 AC: 4699 AN: 4826

European-Finnish (FIN) AF: 0.882 AC: 9337 AN: 10592

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58769 AN: 68020

Other (OTH) AF: 0.937 AC: 1981 AN: 2114

Alfa AF: 0.892 Hom.: 55845

Bravo AF: 0.921

Asia WGS AF: 0.981 AC: 3413 AN: 3478

EpiCase AF: 0.882

EpiControl AF: 0.889

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.7
DANN	Benign	0.74
PhyloP100		0.34
Mutation Taster		=99/1	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: rs1044506; hg19: chr6-32172065;