6-32197667-A-G

Variant names:

• chr6-32197667-A-G
• rs2071278
• NM_004557.4:c.4757-73T>C

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.4757-73T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,365,258 control chromosomes in the GnomAD database, including 16,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1428 hom., cov: 33)
  • Exomes 𝑓: 0.15 (15103 hom.)
• Consequence: NOTCH4 NM_004557.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.267
• Publications: 66 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=-0.91).
• BP6: Variant 6-32197667-A-G is Benign according to our data. Variant chr6-32197667-A-G is described in ClinVar as Benign. ClinVar VariationId is 1179245.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 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.4757-73T>C		intron	N/A	NP_004548.3
	NOTCH4	NR_134949.2		n.4465-73T>C		intron	N/A
	NOTCH4	NR_134950.2		n.4363-73T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH4	ENST00000375023.3	TSL:1 MANE Select	c.4757-73T>C		intron	N/A	ENSP00000364163.3
	NOTCH4	ENST00000474612.1	TSL:5	n.3418-73T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19773 AN: 152140 Hom.: 1431 Cov.: 33

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0936

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.115

GnomAD4 exome AF: 0.153 AC: 185325 AN: 1212998 Hom.: 15103 AF XY: 0.152 AC XY: 90635 AN XY: 598204

African (AFR) AF: 0.0877 AC: 2275 AN: 25948

American (AMR) AF: 0.0962 AC: 2417 AN: 25134

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 2654 AN: 18806

East Asian (EAS) AF: 0.185 AC: 6301 AN: 34062

South Asian (SAS) AF: 0.122 AC: 7953 AN: 65026

European-Finnish (FIN) AF: 0.138 AC: 6802 AN: 49302

Middle Eastern (MID) AF: 0.0707 AC: 358 AN: 5064

European-Non Finnish (NFE) AF: 0.158 AC: 148680 AN: 938936

Other (OTH) AF: 0.155 AC: 7885 AN: 50720

GnomAD4 genome AF: 0.130 AC: 19767 AN: 152260 Hom.: 1428 Cov.: 33 AF XY: 0.129 AC XY: 9619 AN XY: 74466

African (AFR) AF: 0.0960 AC: 3991 AN: 41552

American (AMR) AF: 0.0933 AC: 1428 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 475 AN: 3472

East Asian (EAS) AF: 0.203 AC: 1049 AN: 5180

South Asian (SAS) AF: 0.161 AC: 778 AN: 4826

European-Finnish (FIN) AF: 0.142 AC: 1509 AN: 10606

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10185 AN: 68000

Other (OTH) AF: 0.115 AC: 243 AN: 2116

Alfa AF: 0.150 Hom.: 6875

Bravo AF: 0.124

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.2
DANN	Benign	0.61
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2071278; hg19: chr6-32165444; COSMIC: COSV66681756; COSMIC: COSV66681756;