6-32222629-A-G

Variant names:

• chr6-32222629-A-G
• rs443198
• NM_004557.4:c.333T>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.333T>C​(p.Gly111Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,605,374 control chromosomes in the GnomAD database, including 129,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12343 hom., cov: 32)
  • Exomes 𝑓: 0.40 (116984 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.87
• Publications: 79 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=-0.95).
• BP6: Variant 6-32222629-A-G is Benign according to our data. Variant chr6-32222629-A-G is described in ClinVar as Benign. ClinVar VariationId is 1293220.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004557.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	NM_004557.4	MANE Select	c.333T>C	p.Gly111Gly	synonymous	Exon 3 of 30	NP_004548.3
	NOTCH4	NR_134949.2		n.472T>C		non_coding_transcript_exon	Exon 3 of 30
	NOTCH4	NR_134950.2		n.472T>C		non_coding_transcript_exon	Exon 3 of 29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.333T>C	p.Gly111Gly	synonymous	Exon 3 of 30	ENSP00000364163.3
	NOTCH4	ENST00000473562.1	TSL:1	n.462T>C		non_coding_transcript_exon	Exon 3 of 11

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60110 AN: 151912 Hom.: 12340 Cov.: 32

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.408

GnomAD2 exomes AF: 0.376 AC: 91467 AN: 243264 AF XY: 0.380

Gnomad AFR exome AF: 0.468

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.442

Gnomad EAS exome AF: 0.498

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.379

GnomAD4 exome AF: 0.396 AC: 575338 AN: 1453344 Hom.: 116984 Cov.: 46 AF XY: 0.397 AC XY: 287158 AN XY: 723178

African (AFR) AF: 0.469 AC: 15393 AN: 32802

American (AMR) AF: 0.343 AC: 14305 AN: 41662

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 11593 AN: 25642

East Asian (EAS) AF: 0.526 AC: 20817 AN: 39574

South Asian (SAS) AF: 0.464 AC: 39583 AN: 85282

European-Finnish (FIN) AF: 0.235 AC: 12544 AN: 53346

Middle Eastern (MID) AF: 0.409 AC: 2338 AN: 5718

European-Non Finnish (NFE) AF: 0.391 AC: 433796 AN: 1109286

Other (OTH) AF: 0.416 AC: 24969 AN: 60032

GnomAD4 genome AF: 0.396 AC: 60151 AN: 152030 Hom.: 12343 Cov.: 32 AF XY: 0.391 AC XY: 29025 AN XY: 74304

African (AFR) AF: 0.462 AC: 19183 AN: 41480

American (AMR) AF: 0.363 AC: 5553 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1559 AN: 3472

East Asian (EAS) AF: 0.536 AC: 2749 AN: 5126

South Asian (SAS) AF: 0.485 AC: 2342 AN: 4828

European-Finnish (FIN) AF: 0.239 AC: 2535 AN: 10592

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24891 AN: 67936

Other (OTH) AF: 0.407 AC: 855 AN: 2102

Alfa AF: 0.378 Hom.: 37611

Bravo AF: 0.413

Asia WGS AF: 0.431 AC: 1502 AN: 3478

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: 31705708, 12589427)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.38
DANN	Benign	0.50
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs443198; hg19: chr6-32190406; COSMIC: COSV66678412;