chr8-31640175-C-T

Variant names:

• chr8-31640175-C-T
• rs367543155
• ENST00000520407.5:c.191C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_013962.3(NRG1):​c.191C>T​(p.Ser64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000264 in 1,186,104 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: NRG1 NM_013962.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 2.42
• Publications: 0 publications found

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]

NRG1 Gene-Disease associations (from GenCC):

• schizophrenia 6

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000302325 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076619685).
• BP6: Variant 8-31640175-C-T is Benign according to our data. Variant chr8-31640175-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 98386.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013962.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_013962.3		c.191C>T	p.Ser64Leu	missense	Exon 1 of 5	NP_039256.2	Q02297-9
	NRG1	NM_001159999.3		c.37+744C>T		intron	N/A	NP_001153471.1	A0A494C1F5
	NRG1	NM_001159995.3		c.37+744C>T		intron	N/A	NP_001153467.1	A0A494C1F8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000520407.5	TSL:1	c.191C>T	p.Ser64Leu	missense	Exon 1 of 5	ENSP00000434640.1	Q02297-9
	NRG1	ENST00000650866.1		c.37+744C>T		intron	N/A	ENSP00000499045.1	A0A494C1F5
	NRG1	ENST00000652698.1		c.37+744C>T		intron	N/A	ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes AF: 0.000128 AC: 19 AN: 148450 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000180

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000561 AC: 4 AN: 7136 AF XY: 0.000678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000659

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 294 AN: 1037548 Hom.: 2 Cov.: 34 AF XY: 0.000323 AC XY: 160 AN XY: 495684

African (AFR) AF: 0.0000487 AC: 1 AN: 20548

American (AMR) AF: 0.00 AC: 0 AN: 7150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11810

East Asian (EAS) AF: 0.00 AC: 0 AN: 21670

South Asian (SAS) AF: 0.00327 AC: 78 AN: 23830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18926

Middle Eastern (MID) AF: 0.000353 AC: 1 AN: 2836

European-Non Finnish (NFE) AF: 0.000228 AC: 203 AN: 891630

Other (OTH) AF: 0.000281 AC: 11 AN: 39148

GnomAD4 genome AF: 0.000128 AC: 19 AN: 148556 Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 8 AN XY: 72408

African (AFR) AF: 0.00 AC: 0 AN: 41234

American (AMR) AF: 0.00 AC: 0 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000180 AC: 12 AN: 66486

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.000265 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.00109 AC: 16

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.34	T
PhyloP100		2.4
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		0.16	B
Vest4		0.27
MutPred		0.21		Loss of glycosylation at S64 (P = 0.0037)
MVP		0.53
ClinPred		0.17	T
GERP RS		1.8
PromoterAI		-0.0012	Neutral
Mutation Taster		=88/12	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs367543155; hg19: chr8-31497691;