rs774128685

Variant names:

• chr17-44352375-C-A
• rs774128685
• NM_002087.4:c.1448C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-44352375-C-A
• chr17-44352375-C-G
• chr17-44352375-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002087.4(GRN):​c.1448C>A​(p.Pro483Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P483L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GRN NM_002087.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.68
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4	c.1448C>A	p.Pro483Gln	missense_variant	Exon 12 of 13	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.1448C>A	p.Pro483Gln	missense_variant	Exon 12 of 13	1	NM_002087.4	ENSP00000053867.2
GRN	ENST00000589265.5	c.977C>A	p.Pro326Gln	missense_variant	Exon 8 of 9	5		ENSP00000467616.1
GRN	ENST00000586443.1	c.887C>A	p.Pro296Gln	missense_variant	Exon 7 of 7	3		ENSP00000465673.1
GRN	ENST00000586242.1	c.80C>A	p.Pro27Gln	missense_variant	Exon 2 of 3	3		ENSP00000467837.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461364 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727018

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.5	M;.
PhyloP100		7.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.4	D;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.95		Loss of disorder (P = 0.2447);.;
MVP		0.95
MPC		0.83
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.90
gMVP		0.99
Mutation Taster		=44/56	disease causing

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: rs774128685; hg19: chr17-42429743;