6-32197097-C-A

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.5053-25G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,606,478 control chromosomes in the GnomAD database, including 59,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4935 hom., cov: 32)
  • Exomes 𝑓: 0.26 (54151 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.696

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 (BayesDel_noAF=-0.83).
• BP6: Variant 6-32197097-C-A is Benign according to our data. Variant chr6-32197097-C-A is described in ClinVar as [Benign]. Clinvar id is 1287426.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.5053-25G>T		intron_variant		ENST00000375023.3
NOTCH4	NR_134949.2	n.4761-25G>T		intron_variant, non_coding_transcript_variant
NOTCH4	NR_134950.2	n.4659-25G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.5053-25G>T		intron_variant		1	NM_004557.4	P1
NOTCH4	ENST00000474612.1	n.3714-25G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36639 AN: 151716 Hom.: 4934 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.270

GnomAD3 exomes AF: 0.284 AC: 69127 AN: 243714 Hom.: 10737 AF XY: 0.296 AC XY: 39374 AN XY: 132968

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.364

Gnomad FIN exome AF: 0.268

Gnomad NFE exome AF: 0.291

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.263 AC: 382024 AN: 1454644 Hom.: 54151 Cov.: 34 AF XY: 0.270 AC XY: 195341 AN XY: 723600

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.477

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.262

Gnomad4 NFE exome AF: 0.255

Gnomad4 OTH exome AF: 0.260

GnomAD4 genome AF: 0.241 AC: 36650 AN: 151834 Hom.: 4935 Cov.: 32 AF XY: 0.244 AC XY: 18129 AN XY: 74204

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.305

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.272

Alfa AF: 0.286 Hom.: 4488

Bravo AF: 0.238

Asia WGS AF: 0.254 AC: 890 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 13, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.98
Dann	Benign	0.81

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: rs2071279; hg19: chr6-32164874; COSMIC: COSV66678347; COSMIC: COSV66678347;