Variant 15-75961912-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138573.4(NRG4):c.167A>C(p.Gln56Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,613,734 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 2 hom. )

Consequence

NRG4
NM_138573.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.26

Variant links:

Genes affected

NRG4 (HGNC:29862): (neuregulin 4) The neuregulins, including NRG4, activate type-1 growth factor receptors (see EGFR; MIM 131550) to initiating cell-to-cell signaling through tyrosine phosphorylation (Harari et al., 1999 [PubMed 10348342]).[supplied by OMIM, Mar 2008]

NRG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0729543).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG4	NM_138573.4 linkuse as main transcript	c.167A>C	p.Gln56Pro	missense_variant	4/6	ENST00000394907.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG4	ENST00000394907.8 linkuse as main transcript	c.167A>C	p.Gln56Pro	missense_variant	4/6	1	NM_138573.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251394

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461368

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000988

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.167A>C (p.Q56P) alteration is located in exon 4 (coding exon 3) of the NRG4 gene. This alteration results from a A to C substitution at nucleotide position 167, causing the glutamine (Q) at amino acid position 56 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.073

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.11

Sift

Benign

0.20

T;T

Sift4G

Benign

0.095

T;.

Polyphen

0.0020

B;.

Vest4

0.50

MutPred

0.22

Gain of glycosylation at T57 (P = 0.0513);Gain of glycosylation at T57 (P = 0.0513);

MVP

0.030

MPC

0.37

ClinPred

0.062

GERP RS

2.6

Varity_R

0.26

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over