chr17-44351170-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002087.4(GRN):c.835+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0648 in 1,614,032 control chromosomes in the GnomAD database, including 4,152 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 250 hom., cov: 33)

Exomes 𝑓: 0.067 ( 3902 hom. )

Consequence

GRN
NM_002087.4 splice_region, intron

Scores

Splicing: ADA: 0.0001328

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0320

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

frontotemporal dementia and/or amyotrophic lateral sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
neuronal ceroid lipofuscinosis 11
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P, Orphanet

GRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 17-44351170-G-A is Benign according to our data. Variant chr17-44351170-G-A is described in ClinVar as Benign. ClinVar VariationId is 258553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002087.4. 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
	GRN	NM_002087.4	MANE Select	c.835+7G>A		splice_region intron	N/A	NP_002078.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GRN	ENST00000053867.8	TSL:1 MANE Select	c.835+7G>A	splice_region intron	N/A	ENSP00000053867.2
GRN	ENST00000900927.1		c.835+7G>A	splice_region intron	N/A	ENSP00000570986.1
GRN	ENST00000900929.1		c.835+7G>A	splice_region intron	N/A	ENSP00000570988.1

Frequencies

GnomAD3 genomes

AF:

0.0461

AC:

7013

AN:

152210

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.164

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.0531

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0759

Gnomad OTH

AF:

0.0311

GnomAD2 exomes

AF:

0.0455

AC:

11432

AN:

251256

AF XY:

0.0451

show subpopulations

Gnomad AFR exome

AF:

0.0122

Gnomad AMR exome

AF:

0.0174

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0528

Gnomad NFE exome

AF:

0.0771

Gnomad OTH exome

AF:

0.0429

GnomAD4 exome

AF:

0.0668

AC:

97640

AN:

1461704

Hom.:

3902

Cov.:

AF XY:

0.0645

AC XY:

46916

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0100

AC:

336

AN:

33480

American (AMR)

AF:

0.0169

AC:

754

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

430

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0115

AC:

993

AN:

86256

European-Finnish (FIN)

AF:

0.0574

AC:

3062

AN:

53366

Middle Eastern (MID)

AF:

0.00693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0798

AC:

88750

AN:

1111896

Other (OTH)

AF:

0.0542

AC:

3272

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5239

10478

15717

20956

26195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3202

6404

9606

12808

16010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0460

AC:

7008

AN:

152328

Hom.:

250

Cov.:

AF XY:

0.0435

AC XY:

3237

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0134

AC:

557

AN:

41574

American (AMR)

AF:

0.0255

AC:

391

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0118

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0531

AC:

564

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0759

AC:

5160

AN:

68004

Other (OTH)

AF:

0.0303

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

356

712

1068

1424

1780

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0609

Hom.:

230

Bravo

AF:

0.0423

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (2)

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.1

(source)

DANN

Benign

0.86

PhyloP100

0.032

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over