rs8192585

chr6-32221046-G-Achr6-32221046-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004557.4(NOTCH4):c.731C>T(p.Ser244Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 1,611,614 control chromosomes in the GnomAD database, including 1,522 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.035 (117 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1405 hom.)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.69

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051605105).
• BP6: Variant 6-32221046-G-A is Benign according to our data. Variant chr6-32221046-G-A is described in ClinVar as [Benign]. Clinvar id is 1232512.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0349 (5320/152280) while in subpopulation NFE AF= 0.0456 (3099/67990). AF 95% confidence interval is 0.0442. There are 117 homozygotes in gnomad4. There are 2640 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 5312 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.731C>T	p.Ser244Leu	missense_variant	4/30	ENST00000375023.3
NOTCH4	NR_134949.2	n.870C>T		non_coding_transcript_exon_variant	4/30
NOTCH4	NR_134950.2	n.870C>T		non_coding_transcript_exon_variant	4/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.731C>T	p.Ser244Leu	missense_variant	4/30	1	NM_004557.4	P1
NOTCH4	ENST00000473562.1	n.860C>T		non_coding_transcript_exon_variant	4/11	1

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5312 AN: 152162 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.0547

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0357 AC: 8771 AN: 245824 Hom.: 198 AF XY: 0.0356 AC XY: 4770 AN XY: 133854

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.00924

Gnomad EAS exome AF: 0.0179

Gnomad SAS exome AF: 0.0294

Gnomad FIN exome AF: 0.0554

Gnomad NFE exome AF: 0.0438

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0417 AC: 60837 AN: 1459334 Hom.: 1405 Cov.: 55 AF XY: 0.0415 AC XY: 30155 AN XY: 725760

Gnomad4 AFR exome AF: 0.0189

Gnomad4 AMR exome AF: 0.0278

Gnomad4 ASJ exome AF: 0.00961

Gnomad4 EAS exome AF: 0.0308

Gnomad4 SAS exome AF: 0.0300

Gnomad4 FIN exome AF: 0.0568

Gnomad4 NFE exome AF: 0.0448

Gnomad4 OTH exome AF: 0.0335

GnomAD4 genome AF: 0.0349 AC: 5320 AN: 152280 Hom.: 117 Cov.: 33 AF XY: 0.0355 AC XY: 2640 AN XY: 74464

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0547

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0389 Hom.: 272

Bravo AF: 0.0308

TwinsUK AF: 0.0515 AC: 191

ALSPAC AF: 0.0407 AC: 157

ESP6500AA AF: 0.0172 AC: 52

ESP6500EA AF: 0.0382 AC: 207

ExAC AF: 0.0351 AC: 4217

Asia WGS AF: 0.0250 AC: 86 AN: 3476

EpiCase AF: 0.0415

EpiControl AF: 0.0420

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

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 19197363) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.011
Dann	Benign	0.54
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.8	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.22
Sift	Benign	0.68	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.044
MPC		0.16
ClinPred		0.011	T
GERP RS		-6.9
Varity_R		0.036
gMVP		0.32

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: rs8192585; hg19: chr6-32188823; COSMIC: COSV66681518;