6-32197022-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_004557.4(NOTCH4):c.5103G>A(p.Gly1701=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,612,940 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (11 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.318

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-32197022-C-T is Benign according to our data. Variant chr6-32197022-C-T is described in ClinVar as [Benign]. Clinvar id is 735623.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.318 with no splicing effect.
• BS2: High AC in GnomAd at 162 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.5103G>A	p.Gly1701=	synonymous_variant	28/30	ENST00000375023.3
NOTCH4	NR_134949.2	n.4811G>A		non_coding_transcript_exon_variant	28/30
NOTCH4	NR_134950.2	n.4709G>A		non_coding_transcript_exon_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.5103G>A	p.Gly1701=	synonymous_variant	28/30	1	NM_004557.4	P1
NOTCH4	ENST00000474612.1	n.3764G>A		non_coding_transcript_exon_variant	8/10	5
NOTCH4	ENST00000491215.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152154 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00636

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00192 AC: 473 AN: 246562 Hom.: 4 AF XY: 0.00216 AC XY: 290 AN XY: 134374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00792

Gnomad EAS exome AF: 0.00498

Gnomad SAS exome AF: 0.00523

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00110 AC: 1614 AN: 1460668 Hom.: 11 Cov.: 32 AF XY: 0.00128 AC XY: 931 AN XY: 726648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00861

Gnomad4 EAS exome AF: 0.00277

Gnomad4 SAS exome AF: 0.00566

Gnomad4 FIN exome AF: 0.0000766

Gnomad4 NFE exome AF: 0.000527

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152272 Hom.: 3 Cov.: 32 AF XY: 0.00111 AC XY: 83 AN XY: 74458

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.00637

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00102

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 24, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	8.2
Dann	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs142586922; hg19: chr6-32164799;