chr17-44349572-G-A

Variant names:

• chr17-44349572-G-A
• rs9897526
• NM_002087.4:c.264+21G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002087.4(GRN):​c.264+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,786 control chromosomes in the GnomAD database, including 19,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4235 hom., cov: 33)
  • Exomes 𝑓: 0.13 (15627 hom.)
• Consequence: GRN NM_002087.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.99
• Publications: 28 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-44349572-G-A is Benign according to our data. Variant chr17-44349572-G-A is described in ClinVar as Benign. ClinVar VariationId is 558916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.387 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	NM_002087.4	MANE Select	c.264+21G>A		intron	N/A	NP_002078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	ENST00000053867.8	TSL:1 MANE Select	c.264+21G>A		intron	N/A	ENSP00000053867.2
	GRN	ENST00000900927.1		c.264+21G>A		intron	N/A	ENSP00000570986.1
	GRN	ENST00000900929.1		c.264+21G>A		intron	N/A	ENSP00000570988.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30343 AN: 152128 Hom.: 4203 Cov.: 33

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0898

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.159 AC: 39920 AN: 250706 AF XY: 0.163

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0924

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.131 AC: 190911 AN: 1461540 Hom.: 15627 Cov.: 34 AF XY: 0.135 AC XY: 98345 AN XY: 727118

African (AFR) AF: 0.405 AC: 13560 AN: 33478

American (AMR) AF: 0.125 AC: 5611 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3679 AN: 26134

East Asian (EAS) AF: 0.0904 AC: 3587 AN: 39700

South Asian (SAS) AF: 0.307 AC: 26473 AN: 86248

European-Finnish (FIN) AF: 0.120 AC: 6411 AN: 53324

Middle Eastern (MID) AF: 0.211 AC: 1216 AN: 5768

European-Non Finnish (NFE) AF: 0.109 AC: 121039 AN: 1111782

Other (OTH) AF: 0.155 AC: 9335 AN: 60382

GnomAD4 genome AF: 0.200 AC: 30424 AN: 152246 Hom.: 4235 Cov.: 33 AF XY: 0.201 AC XY: 14958 AN XY: 74456

African (AFR) AF: 0.392 AC: 16259 AN: 41516

American (AMR) AF: 0.137 AC: 2092 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 492 AN: 3470

East Asian (EAS) AF: 0.0901 AC: 467 AN: 5186

South Asian (SAS) AF: 0.324 AC: 1563 AN: 4828

European-Finnish (FIN) AF: 0.123 AC: 1305 AN: 10612

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7741 AN: 68018

Other (OTH) AF: 0.181 AC: 382 AN: 2114

Alfa AF: 0.143 Hom.: 2364

Bravo AF: 0.203

Asia WGS AF: 0.241 AC: 838 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (1)
-	-	1	Neuronal ceroid lipofuscinosis 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.019
DANN	Benign	0.46
PhyloP100		-2.0
PromoterAI		0.0068	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9897526; hg19: chr17-42426940; COSMIC: COSV50010157; COSMIC: COSV50010157;