rs8192583

chr6-32195497-G-Achr6-32195497-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_004557.4(NOTCH4):c.5952C>T(p.Asp1984=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,612,868 control chromosomes in the GnomAD database, including 1,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (164 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1594 hom.)
• Consequence: NOTCH4 NM_004557.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.713

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]

GPSM3 (HGNC:13945): (G protein signaling modulator 3) Predicted to enable GTPase regulator activity. Predicted to be involved in positive regulation of inflammatory response. Predicted to act upstream of or within positive regulation of cytokine production involved in inflammatory response and positive regulation of leukocyte chemotaxis. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-32195497-G-A is Benign according to our data. Variant chr6-32195497-G-A is described in ClinVar as [Benign]. Clinvar id is 1232666.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.713 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH4	NM_004557.4	c.5952C>T	p.Asp1984=	synonymous_variant	30/30	ENST00000375023.3
GPSM3	NM_022107.3	c.-347C>T		5_prime_UTR_variant	1/8
NOTCH4	NR_134949.2	n.5660C>T		non_coding_transcript_exon_variant	30/30
NOTCH4	NR_134950.2	n.5558C>T		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH4	ENST00000375023.3	c.5952C>T	p.Asp1984=	synonymous_variant	30/30	1	NM_004557.4	P1
GPSM3	ENST00000375043.3	c.-347C>T		5_prime_UTR_variant	1/8	1		P1
NOTCH4	ENST00000474612.1	n.4613C>T		non_coding_transcript_exon_variant	10/10	5
NOTCH4	ENST00000491215.1	n.978C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6433 AN: 152208 Hom.: 166 Cov.: 32

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.0592

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0468

Gnomad OTH AF: 0.0430

GnomAD3 exomes AF: 0.0354 AC: 8705 AN: 245784 Hom.: 220 AF XY: 0.0374 AC XY: 5013 AN XY: 133984

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00443

Gnomad SAS exome AF: 0.0560

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0437 AC: 63881 AN: 1460542 Hom.: 1594 Cov.: 31 AF XY: 0.0437 AC XY: 31747 AN XY: 726584

Gnomad4 AFR exome AF: 0.0569

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.0535

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.0470

Gnomad4 OTH exome AF: 0.0424

GnomAD4 genome AF: 0.0422 AC: 6426 AN: 152326 Hom.: 164 Cov.: 32 AF XY: 0.0405 AC XY: 3020 AN XY: 74490

Gnomad4 AFR AF: 0.0501

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00888

Gnomad4 SAS AF: 0.0586

Gnomad4 FIN AF: 0.0175

Gnomad4 NFE AF: 0.0468

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0412 Hom.: 70

Bravo AF: 0.0431

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0458

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 05, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.24
Dann	Benign	0.80

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: rs8192583; hg19: chr6-32163274; COSMIC: COSV66678918; COSMIC: COSV66678918;