rs375439809

chr17-44349731-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002087.4(GRN):c.329G>A(p.Arg110Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000069 in 1,609,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: GRN NM_002087.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.48

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01883328).
• BP6: Variant 17-44349731-G-A is Benign according to our data. Variant chr17-44349731-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 589177.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000666 (97/1456986) while in subpopulation MID AF= 0.000348 (2/5752). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4_exome. There are 53 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.329G>A	p.Arg110Gln	missense_variant	4/13	ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.329G>A	p.Arg110Gln	missense_variant	4/13	1	NM_002087.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000918 AC: 23 AN: 250476 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135532

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000666 AC: 97 AN: 1456986 Hom.: 0 Cov.: 31 AF XY: 0.0000731 AC XY: 53 AN XY: 725188

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000478

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74514

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 110 of the GRN protein (p.Arg110Gln). This variant is present in population databases (rs375439809, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of frontotemporal dementia or amyotrophic lateral sclerosis (PMID: 18184915, 29525180, 30279455, 32028661). ClinVar contains an entry for this variant (Variation ID: 589177). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.49
Dann	Benign	0.82
DEOGEN2	Benign	0.059	T;.;.;T;.;T;T;T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.37	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.019	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.27	N;.;.;.;.;.;.;.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.51	N;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.53	T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T;T;.
Polyphen		0.0	B;.;.;.;.;.;.;.;.;.
Vest4		0.18
MVP		0.37
MPC		0.27
ClinPred		0.0070	T
GERP RS		-8.2
Varity_R		0.019
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375439809; hg19: chr17-42427099;