Genetic Variant GRN:c.-8+963A>G (chr17-44346297-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002087.4(GRN):c.-8+963A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 152,082 control chromosomes in the GnomAD database, including 6,625 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 6612 hom., cov: 31)

Exomes 𝑓: 0.31 ( 13 hom. )

Consequence

GRN
NM_002087.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.792

Variant links:

Genes affected

GRN (HGNC:4601): (granulin precursor) Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis. [provided by RefSeq, Jul 2008]

GRN links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4 link	c.-8+963A>G		intron_variant	Intron 1 of 12	ENST00000053867.8	NP_002078.1	P28799-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 link	c.-8+963A>G		intron_variant	Intron 1 of 12	1	NM_002087.4	ENSP00000053867.2		P28799-1

Frequencies

GnomAD3 genomes

AF:

0.285

AC:

43338

AN:

151802

Hom.:

6609

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.209

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.587

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.350

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.269

Gnomad OTH

AF:

0.263

GnomAD4 exome

AF:

0.315

AC:

AN:

162

Hom.:

AF XY:

0.260

AC XY:

AN XY:

104

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.714

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.226

AC:

AN:

106

Other (OTH)

AF:

0.375

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.285

AC:

43352

AN:

151920

Hom.:

6612

Cov.:

AF XY:

0.295

AC XY:

21872

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.239

AC:

9909

AN:

41412

American (AMR)

AF:

0.313

AC:

4772

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

823

AN:

3472

East Asian (EAS)

AF:

0.587

AC:

3019

AN:

5140

South Asian (SAS)

AF:

0.423

AC:

2034

AN:

4810

European-Finnish (FIN)

AF:

0.350

AC:

3695

AN:

10564

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.269

AC:

18288

AN:

67944

Other (OTH)

AF:

0.263

AC:

555

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1527

3055

4582

6110

7637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.276

Hom.:

24125

Bravo

AF:

0.280

Asia WGS

AF:

0.486

AC:

1686

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.0

(source)

DANN

Benign

0.83

PhyloP100

-0.79

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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chr17-44346297-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over