6-32222440-T-C

Variant names:

• chr6-32222440-T-C
• rs915895
• NM_004557.4:c.451+71A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004557.4(NOTCH4):​c.451+71A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,348,358 control chromosomes in the GnomAD database, including 86,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (9272 hom., cov: 33)
  • Exomes 𝑓: 0.35 (76732 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.786
• Publications: 29 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 6-32222440-T-C is Benign according to our data. Variant chr6-32222440-T-C is described in ClinVar as Benign. ClinVar VariationId is 1258307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.503 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.451+71A>G		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.590+71A>G		intron	N/A
	NOTCH4	NR_134950.2		n.590+71A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.451+71A>G		intron	N/A	ENSP00000364163.3
	NOTCH4	ENST00000473562.1	TSL:1	n.580+71A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52291 AN: 152026 Hom.: 9272 Cov.: 33

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.356

GnomAD4 exome AF: 0.353 AC: 422384 AN: 1196214 Hom.: 76732 AF XY: 0.353 AC XY: 205248 AN XY: 580844

African (AFR) AF: 0.375 AC: 9307 AN: 24822

American (AMR) AF: 0.305 AC: 4457 AN: 14618

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 6986 AN: 17548

East Asian (EAS) AF: 0.521 AC: 16048 AN: 30822

South Asian (SAS) AF: 0.396 AC: 20918 AN: 52834

European-Finnish (FIN) AF: 0.225 AC: 10174 AN: 45148

Middle Eastern (MID) AF: 0.380 AC: 1273 AN: 3346

European-Non Finnish (NFE) AF: 0.350 AC: 334666 AN: 957234

Other (OTH) AF: 0.372 AC: 18555 AN: 49842

GnomAD4 genome AF: 0.344 AC: 52307 AN: 152144 Hom.: 9272 Cov.: 33 AF XY: 0.340 AC XY: 25307 AN XY: 74360

African (AFR) AF: 0.378 AC: 15670 AN: 41504

American (AMR) AF: 0.298 AC: 4553 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1348 AN: 3462

East Asian (EAS) AF: 0.519 AC: 2687 AN: 5174

South Asian (SAS) AF: 0.438 AC: 2116 AN: 4826

European-Finnish (FIN) AF: 0.235 AC: 2486 AN: 10600

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22287 AN: 67964

Other (OTH) AF: 0.357 AC: 754 AN: 2112

Alfa AF: 0.341 Hom.: 31640

Bravo AF: 0.354

Asia WGS AF: 0.391 AC: 1356 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.1
DANN	Benign	0.75
PhyloP100		-0.79
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: rs915895; hg19: chr6-32190217; COSMIC: COSV66684828;