NM_002087.4:c.1544G>C

Variant names:

• chr17-44352471-G-C
• rs25647
• NM_002087.4:c.1544G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002087.4(GRN):​c.1544G>C​(p.Gly515Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,046 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: GRN NM_002087.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -1.05
• Publications: 16 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 (MetaRNN=0.0036056936).
• BP6: Variant 17-44352471-G-C is Benign according to our data. Variant chr17-44352471-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 98189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00798 (1216/152312) while in subpopulation AFR AF = 0.0269 (1117/41568). AF 95% confidence interval is 0.0256. There are 20 homozygotes in GnomAd4. There are 569 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,AD gene

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.1544G>C	p.Gly515Ala	missense	Exon 12 of 13	NP_002078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	ENST00000053867.8	TSL:1 MANE Select	c.1544G>C	p.Gly515Ala	missense	Exon 12 of 13	ENSP00000053867.2
	GRN	ENST00000900927.1		c.1544G>C	p.Gly515Ala	missense	Exon 12 of 13	ENSP00000570986.1
	GRN	ENST00000900929.1		c.1544G>C	p.Gly515Ala	missense	Exon 13 of 14	ENSP00000570988.1

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 1206 AN: 152194 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00225 AC: 565 AN: 251388 AF XY: 0.00178

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00106 AC: 1553 AN: 1461734 Hom.: 23 Cov.: 34 AF XY: 0.000934 AC XY: 679 AN XY: 727172

African (AFR) AF: 0.0293 AC: 982 AN: 33476

American (AMR) AF: 0.00208 AC: 93 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.000224 AC: 249 AN: 1111942

Other (OTH) AF: 0.00311 AC: 188 AN: 60392

GnomAD4 genome AF: 0.00798 AC: 1216 AN: 152312 Hom.: 20 Cov.: 33 AF XY: 0.00764 AC XY: 569 AN XY: 74498

African (AFR) AF: 0.0269 AC: 1117 AN: 41568

American (AMR) AF: 0.00340 AC: 52 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68006

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00112 Hom.: 1

Bravo AF: 0.00921

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0297 AC: 131

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	2	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (2)
-	-	2	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.83
DANN	Benign	0.85
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-1.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.14	T
Sift4G	Benign	0.56	T
Polyphen		0.50	P
Vest4		0.18
MVP		0.82
MPC		0.25
ClinPred		0.014	T
GERP RS		0.12
PromoterAI		0.0032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.057
gMVP		0.61
Mutation Taster		=96/4	polymorphism

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: rs25647; hg19: chr17-42429839;