rs59793293

Positions:

• chr17-44915252-G-A
• chr17-44915252-G-C
• chr17-44915252-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000588735.3(GFAP):​c.235C>T​(p.Arg79Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R79L) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GFAP ENST00000588735.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 8.00

Genes affected

GFAP (HGNC:4235): (glial fibrillary acidic protein) This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000588735.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44915251-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-44915252-G-A is Pathogenic according to our data. Variant chr17-44915252-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.235C>T	p.Arg79Cys	missense_variant	1/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.235C>T	p.Arg79Cys	missense_variant	1/10		NP_001350775.1
GFAP	NM_001242376.3	c.235C>T	p.Arg79Cys	missense_variant	1/7		NP_001229305.1
GFAP	NM_001131019.3	c.235C>T	p.Arg79Cys	missense_variant	1/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.235C>T	p.Arg79Cys	missense_variant	1/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74514

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2021	Published functional studies demonstrate that p.(R79C) significantly increases GFAP aggregation in zebra fish in comparison to wild-type (Lee et al., 2017) and impairs mitochondrial transfer from astrocytes to neighboring neurons (Gao et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12509855, 23254569, 15696488, 18584981, 12034785, 12175861, 21533827, 11567214, 12581808, 15732097, 19128991, 18463287, 31484723, 33176815, 31327963, 11138011, 33084218, 34146839, 34692893, 17894839, 28882119) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2022	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg79 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 11138011), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GFAP function (PMID: 28882119). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16171). This missense change has been observed in individual(s) with Alexander disease (PMID: 11138011, 18584981, 23254569). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the GFAP protein (p.Arg79Cys). -

Alexander disease Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 25, 2022	The GFAP c.235C>T p.(Arg79Cys) missense variant has been reported in a heterozygous state in at least seven individuals with Alexander disease, including five in whom it occurred in a de novo state (PMID: 11138011; PMID: 15696488; PMID: 18584981; PMID: 23254569; PMID: 31484723; PMID: 33176815). The c.235C>T variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000015 in the European (non-Finnish) population (version 3.1.2). Compared to wild-type GFAP, the p.(Arg79Cys) variant has been shown to significantly increase GFAP aggregation when expressed in zebrafish (PMID: 28882119). Mass spectroscopy studies in a patient with the variant suggested that levels of variant GFAP were lower than those of wild-type, suggesting an intrinsic toxicity of the variant form (PMID: 31484723). When expressed in human pluripotent stem cells induced to differentiate into astrocytes, the variant also impaired mitochondrial transfer from astrocytes and reduced astrocytic CD38 expression (PMID: 31327963). This variant was identified in a de novo state in the proband. Based on the available evidence, the c.235C>T (p.Arg79Cys) variant is classified as pathogenic for Alexander disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;D;.;.;.;D;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;.;H;H;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.0	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.022	.;.;D;D;.;D;D;.;.
Polyphen		0.47	.;P;.;.;.;.;.;.;.
Vest4		0.99, 0.99
MutPred		0.98		Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);Loss of MoRF binding (P = 0.0103);
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.90
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs59793293; hg19: chr17-42992620; COSMIC: COSV99493595; COSMIC: COSV99493595;