6-32221255-T-C

Variant names:

• chr6-32221255-T-C
• rs415929
• NM_004557.4:c.522A>G

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.522A>G​(p.Thr174Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,612,758 control chromosomes in the GnomAD database, including 77,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6956 hom., cov: 32)
  • Exomes 𝑓: 0.31 (70521 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.33
• Publications: 52 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=-0.97).
• BP6: Variant 6-32221255-T-C is Benign according to our data. Variant chr6-32221255-T-C is described in ClinVar as Benign. ClinVar VariationId is 1281290.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH4	NM_004557.4	c.522A>G	p.Thr174Thr	synonymous_variant	Exon 4 of 30	ENST00000375023.3	NP_004548.3
NOTCH4	NR_134949.2	n.661A>G		non_coding_transcript_exon_variant	Exon 4 of 30
NOTCH4	NR_134950.2	n.661A>G		non_coding_transcript_exon_variant	Exon 4 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH4	ENST00000375023.3	c.522A>G	p.Thr174Thr	synonymous_variant	Exon 4 of 30	1	NM_004557.4	ENSP00000364163.3
NOTCH4	ENST00000473562.1	n.651A>G		non_coding_transcript_exon_variant	Exon 4 of 11	1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44557 AN: 151980 Hom.: 6953 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.310 AC: 75823 AN: 244230 AF XY: 0.320

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.265

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.191

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.305 AC: 445874 AN: 1460660 Hom.: 70521 Cov.: 52 AF XY: 0.309 AC XY: 224471 AN XY: 726658

African (AFR) AF: 0.218 AC: 7300 AN: 33480

American (AMR) AF: 0.269 AC: 12031 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 13107 AN: 26134

East Asian (EAS) AF: 0.271 AC: 10762 AN: 39700

South Asian (SAS) AF: 0.335 AC: 28854 AN: 86258

European-Finnish (FIN) AF: 0.309 AC: 16155 AN: 52306

Middle Eastern (MID) AF: 0.398 AC: 2293 AN: 5768

European-Non Finnish (NFE) AF: 0.303 AC: 336431 AN: 1111910

Other (OTH) AF: 0.314 AC: 18941 AN: 60384

GnomAD4 genome AF: 0.293 AC: 44562 AN: 152098 Hom.: 6956 Cov.: 32 AF XY: 0.294 AC XY: 21860 AN XY: 74362

African (AFR) AF: 0.212 AC: 8800 AN: 41514

American (AMR) AF: 0.322 AC: 4928 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1760 AN: 3472

East Asian (EAS) AF: 0.225 AC: 1161 AN: 5162

South Asian (SAS) AF: 0.321 AC: 1547 AN: 4822

European-Finnish (FIN) AF: 0.314 AC: 3315 AN: 10574

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21896 AN: 67950

Other (OTH) AF: 0.316 AC: 669 AN: 2114

Alfa AF: 0.318 Hom.: 34024

Bravo AF: 0.288

Asia WGS AF: 0.347 AC: 1211 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.362

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.26
DANN	Benign	0.49
PhyloP100		-3.3
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: rs415929; hg19: chr6-32189032; COSMIC: COSV66678403;