17-44913333-C-T

Position:

• chr17-44913333-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_002055.5(GFAP):​c.716G>A​(p.Arg239His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:2
• Conservation: PhyloP100: 7.91

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]

GFAP (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-44913333-C-T is Pathogenic according to our data. Variant chr17-44913333-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16168.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.716G>A	p.Arg239His	missense_variant	4/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.716G>A	p.Arg239His	missense_variant	4/10		NP_001350775.1
GFAP	NM_001242376.3	c.716G>A	p.Arg239His	missense_variant	4/7		NP_001229305.1
GFAP	NM_001131019.3	c.716G>A	p.Arg239His	missense_variant	4/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.716G>A	p.Arg239His	missense_variant	4/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alexander disease Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	in vivo	Laboratory for Animal Genetics, Ghent University	-	Similar disease in dogs: OMIA 001208-9615. Tetraplegia with spastic front limbs mimicking 'swimming puppy syndrome'; detection of GFAP containing Rosenthal fibers in astrocytes; Alexander's disease (AxD) in a Labrador retriever is caused by a heterozygous de novo dominant R240H GFAP mutation, orthologous to the human R239H hotspot mutation known to cause a severe AxD phenotype. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.716G>A;p.(Arg239His) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 16168; NBK1172; OMIM 137780.0001; PMID: 24427505; 17383133; 11567214; 21533827) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 17065456, 23432455 ) - PS3. This variant is not present in population databases:rs59565950, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in GFAP that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4_Moderate+PP4+PM6_Supporting+PS3+PM5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	Reported previously in the heterozygous state in at least one individual with Alexander syndrome (Brenner et al., 2001); Published functional studies demonstrate that mice harboring the R239H variant develop astrocyte pathology typical of Alexander disease (Hagerman et al., 2006; Sosunov et al., 2013; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32180488, 11138011, 31484723, 28882119, 23432455, 24102621, 27966545, 27193225, 28359321, 27609520, 27798231, 27648269, 23616550, 17065456) -

Spastic paraplegia, intellectual disability, nystagmus, and obesity Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Jun 22, 2023

The observed missense c.716G>A(p.Arg239His) variant in GFAP gene has been reported previously in heterozygous state in individual(s) affected with Alexander disease (Viedma-Poyatos et al., 2022). Experimental studies have shown that this p.Arg239His change affects GFAP gene function (Jany et al., 2013; Boczek et al., 2016). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The amino acid Arg at position 239 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg239His in GFAP is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;H;.;.;H;H;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	.;.;D;.;D;.;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	.;.;D;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.95, 0.95, 0.97
MutPred		0.98		Gain of ubiquitination at K236 (P = 0.0856);Gain of ubiquitination at K236 (P = 0.0856);Gain of ubiquitination at K236 (P = 0.0856);.;Gain of ubiquitination at K236 (P = 0.0856);Gain of ubiquitination at K236 (P = 0.0856);Gain of ubiquitination at K236 (P = 0.0856);.;
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.94
gMVP		0.93

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: rs59565950; hg19: chr17-42990701; COSMIC: COSV53652317; COSMIC: COSV53652317;