rs770058074

Variant names:

• chr17-44352365-C-A
• rs770058074
• NM_002087.4:c.1438C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-44352365-C-A
• chr17-44352365-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.1438C>A​(p.His480Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. H480Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRN NM_002087.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.96
• 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, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4	c.1438C>A	p.His480Asn	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.1438C>A	p.His480Asn	missense_variant	Exon 12 of 13	1	NM_002087.4	ENSP00000053867.2
GRN	ENST00000589265.5	c.967C>A	p.His323Asn	missense_variant	Exon 8 of 9	5		ENSP00000467616.1
GRN	ENST00000586443.1	c.877C>A	p.His293Asn	missense_variant	Exon 7 of 7	3		ENSP00000465673.1
GRN	ENST00000586242.1	c.70C>A	p.His24Asn	missense_variant	Exon 2 of 3	3		ENSP00000467837.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.2	M;.
PhyloP100		6.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.5	D;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.86		Gain of disorder (P = 0.1741);.;
MVP		0.88
MPC		0.89
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.0026	Neutral
Varity_R		0.89
gMVP		0.97

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: rs770058074; hg19: chr17-42429733;