rs915894

chr6-32222613-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004557.4(NOTCH4):c.349A>C(p.Lys117Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,601,760 control chromosomes in the GnomAD database, including 116,051 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 0.36 (10078 hom., cov: 32)
  • Exomes 𝑓: 0.38 (105973 hom.)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.03

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=9.202361E-4).
• BP6: Variant 6-32222613-T-G is Benign according to our data. Variant chr6-32222613-T-G is described in ClinVar as [Benign]. Clinvar id is 1294880.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.349A>C	p.Lys117Gln	missense_variant	3/30	ENST00000375023.3
NOTCH4	NR_134949.2	n.488A>C		non_coding_transcript_exon_variant	3/30
NOTCH4	NR_134950.2	n.488A>C		non_coding_transcript_exon_variant	3/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.349A>C	p.Lys117Gln	missense_variant	3/30	1	NM_004557.4	P1
NOTCH4	ENST00000473562.1	n.478A>C		non_coding_transcript_exon_variant	3/11	1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54623 AN: 151886 Hom.: 10078 Cov.: 32

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.348

GnomAD3 exomes AF: 0.352 AC: 84293 AN: 239624 Hom.: 15351 AF XY: 0.355 AC XY: 46162 AN XY: 130052

Gnomad AFR exome AF: 0.382

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.462

Gnomad SAS exome AF: 0.369

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.347

GnomAD4 exome AF: 0.379 AC: 549427 AN: 1449756 Hom.: 105973 Cov.: 43 AF XY: 0.378 AC XY: 272786 AN XY: 721400

Gnomad4 AFR exome AF: 0.376

Gnomad4 AMR exome AF: 0.274

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.505

Gnomad4 SAS exome AF: 0.374

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.373

GnomAD4 genome AF: 0.360 AC: 54652 AN: 152004 Hom.: 10078 Cov.: 32 AF XY: 0.356 AC XY: 26465 AN XY: 74296

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.493

Gnomad4 SAS AF: 0.406

Gnomad4 FIN AF: 0.312

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.346

Alfa AF: 0.366 Hom.: 9085

Bravo AF: 0.364

TwinsUK AF: 0.389 AC: 1444

ALSPAC AF: 0.409 AC: 1576

ESP6500AA AF: 0.378 AC: 1664

ESP6500EA AF: 0.369 AC: 3177

ExAC AF: 0.357 AC: 43354

Asia WGS AF: 0.335 AC: 1166 AN: 3478

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.6
Dann	Benign	0.49
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.043	T
MetaRNN	Benign	0.00092	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.040	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.21
Sift	Benign	0.40	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.19
ClinPred		0.00030	T
GERP RS		2.4
Varity_R		0.086
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs915894; hg19: chr6-32190390; COSMIC: COSV66678407;