6-32220606-T-C

Variant names:

• chr6-32220606-T-C
• rs422951
• NM_004557.4:c.958A>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.958A>G​(p.Thr320Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,226 control chromosomes in the GnomAD database, including 152,441 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (12552 hom., cov: 32)
  • Exomes 𝑓: 0.43 (139889 hom.)
• Consequence: NOTCH4 NM_004557.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.154

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=5.7498703E-5).
• BP6: Variant 6-32220606-T-C is Benign according to our data. Variant chr6-32220606-T-C is described in ClinVar as [Benign]. Clinvar id is 1297197.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.958A>G	p.Thr320Ala	missense_variant	Exon 6 of 30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.1097A>G		non_coding_transcript_exon_variant	Exon 6 of 30
NOTCH4	NR_134950.2	n.1097A>G		non_coding_transcript_exon_variant	Exon 6 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.958A>G	p.Thr320Ala	missense_variant	Exon 6 of 30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.1087A>G		non_coding_transcript_exon_variant	Exon 6 of 11	1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60127 AN: 151664 Hom.: 12551 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.401

GnomAD3 exomes AF: 0.401 AC: 99350 AN: 248050 Hom.: 21484 AF XY: 0.411 AC XY: 55323 AN XY: 134748

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.587

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.407

Gnomad FIN exome AF: 0.427

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.431

GnomAD4 exome AF: 0.432 AC: 631140 AN: 1461444 Hom.: 139889 Cov.: 53 AF XY: 0.433 AC XY: 315121 AN XY: 727010

Gnomad4 AFR exome AF: 0.299

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.583

Gnomad4 EAS exome AF: 0.210

Gnomad4 SAS exome AF: 0.406

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.396 AC: 60133 AN: 151782 Hom.: 12552 Cov.: 32 AF XY: 0.394 AC XY: 29213 AN XY: 74168

Gnomad4 AFR AF: 0.301

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.584

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.411

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.403

Alfa AF: 0.449 Hom.: 21782

Bravo AF: 0.386

TwinsUK AF: 0.434 AC: 1611

ALSPAC AF: 0.433 AC: 1669

ESP6500AA AF: 0.312 AC: 942

ESP6500EA AF: 0.450 AC: 2436

ExAC AF: 0.400 AC: 48465

Asia WGS AF: 0.372 AC: 1301 AN: 3478

EpiCase AF: 0.475

EpiControl AF: 0.477

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

This variant is associated with the following publications: (PMID: 23566281, 23549433, 31838262) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.042
DANN	Benign	0.30
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.046	T
MetaRNN	Benign	0.000057	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.57	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.28
Sift	Benign	0.55	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.18
ClinPred		0.0039	T
GERP RS		-5.0
Varity_R		0.061
gMVP		0.38

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: rs422951; hg19: chr6-32188383; COSMIC: COSV66678386;