chr8-31640334-C-T

Variant names:

• chr8-31640334-C-T
• rs367543157
• ENST00000520407.5:c.350C>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.350C>T​(p.Pro117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,183,460 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (33 hom.)
• Consequence: NRG1 NM_013962.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.333
• Publications: 1 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=0.0071258247).
• BP6: Variant 8-31640334-C-T is Benign according to our data. Variant chr8-31640334-C-T is described in ClinVar as Benign. ClinVar VariationId is 98388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 10 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.350C>T	p.Pro117Leu	missense	Exon 1 of 5	NP_039256.2	Q02297-9
	NRG1	NM_001159999.3		c.37+903C>T		intron	N/A	NP_001153471.1	A0A494C1F5
	NRG1	NM_001159995.3		c.37+903C>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.350C>T	p.Pro117Leu	missense	Exon 1 of 5	ENSP00000434640.1	Q02297-9
	NRG1	ENST00000650866.1		c.37+903C>T		intron	N/A	ENSP00000499045.1	A0A494C1F5
	NRG1	ENST00000652698.1		c.37+903C>T		intron	N/A	ENSP00000499008.1	A0A494C1F8

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 761 AN: 148858 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000934

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00389

Gnomad OTH AF: 0.00292

GnomAD2 exomes AF: 0.0298 AC: 10 AN: 336 AF XY: 0.0326

Gnomad FIN exome AF: 0.0652

Gnomad NFE exome AF: 0.00515

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00416 AC: 4306 AN: 1034500 Hom.: 33 Cov.: 34 AF XY: 0.00408 AC XY: 1994 AN XY: 488960

African (AFR) AF: 0.000715 AC: 15 AN: 20982

American (AMR) AF: 0.00147 AC: 10 AN: 6820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11886

East Asian (EAS) AF: 0.00 AC: 0 AN: 21996

South Asian (SAS) AF: 0.000884 AC: 17 AN: 19228

European-Finnish (FIN) AF: 0.0411 AC: 813 AN: 19784

Middle Eastern (MID) AF: 0.00113 AC: 3 AN: 2648

European-Non Finnish (NFE) AF: 0.00375 AC: 3340 AN: 891266

Other (OTH) AF: 0.00271 AC: 108 AN: 39890

GnomAD4 genome AF: 0.00512 AC: 762 AN: 148960 Hom.: 10 Cov.: 32 AF XY: 0.00698 AC XY: 507 AN XY: 72650

African (AFR) AF: 0.000461 AC: 19 AN: 41190

American (AMR) AF: 0.000933 AC: 14 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.0488 AC: 459 AN: 9406

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.00389 AC: 260 AN: 66792

Other (OTH) AF: 0.00289 AC: 6 AN: 2074

Alfa AF: 0.00381 Hom.: 0

Bravo AF: 0.00186

ExAC AF: 0.00203 AC: 3

ClinVar

ClinVar submissions

Significance: 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	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.91	T
PhyloP100		-0.33
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.019	D
Polyphen		0.062	B
Vest4		0.18
ClinPred		0.078	T
GERP RS		-1.5
PromoterAI		-0.045	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs367543157; hg19: chr8-31497850;