15-75961945-C-A

Position:

• chr15-75961945-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_138573.4(NRG4):​c.134G>T​(p.Cys45Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NRG4 NM_138573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG4	NM_138573.4	c.134G>T	p.Cys45Phe	missense_variant	4/6	ENST00000394907.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG4	ENST00000394907.8	c.134G>T	p.Cys45Phe	missense_variant	4/6	1	NM_138573.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461244 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.134G>T (p.C45F) alteration is located in exon 4 (coding exon 3) of the NRG4 gene. This alteration results from a G to T substitution at nucleotide position 134, causing the cysteine (C) at amino acid position 45 to be replaced by a phenylalanine (F). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.8	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.9	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.96		Loss of phosphorylation at T41 (P = 0.2646);Loss of phosphorylation at T41 (P = 0.2646);
MVP		0.90
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.92
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2032544483; hg19: chr15-76254286;