8-32595840-G-C

Variant names:

• chr8-32595840-G-C
• rs3924999
• NM_013964.5:c.113G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013964.5(NRG1):​c.113G>C​(p.Arg38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,694 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NRG1 NM_013964.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.113G>C	p.Arg38Pro	missense_variant	Exon 2 of 12	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.113G>C	p.Arg38Pro	missense_variant	Exon 2 of 12	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451694 Hom.: 0 Cov.: 35 AF XY: 0.00000277 AC XY: 2 AN XY: 722432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	0.0086	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;.;.;T;.;.;.;.;.;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.49	.;.;.;.;.;N;N;N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D;D;D;D;.;D;D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.86, 0.77, 0.97	.;.;D;.;.;.;P;P;P;D
Vest4		0.48, 0.48, 0.52, 0.45, 0.43, 0.45, 0.46
MutPred		0.55		.;.;.;.;.;Gain of glycosylation at R38 (P = 0.0105);Gain of glycosylation at R38 (P = 0.0105);Gain of glycosylation at R38 (P = 0.0105);Gain of glycosylation at R38 (P = 0.0105);Gain of glycosylation at R38 (P = 0.0105);
MVP		0.45
MPC		0.73
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.77

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3924999; hg19: chr8-32453358;