rs797044569

chr17-44915290-C-Gchr17-44915290-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_002055.5(GFAP):c.197G>C(p.Arg66Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.14

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 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44915290-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190332.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 17-44915290-C-G is Pathogenic according to our data. Variant chr17-44915290-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372607.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.197G>C	p.Arg66Pro	missense_variant	1/9	ENST00000588735.3
GFAP	NM_001363846.2	c.197G>C	p.Arg66Pro	missense_variant	1/10
GFAP	NM_001242376.3	c.197G>C	p.Arg66Pro	missense_variant	1/7
GFAP	NM_001131019.3	c.197G>C	p.Arg66Pro	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.197G>C	p.Arg66Pro	missense_variant	1/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2015

The R66P variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. The R66Pvariant is a non-conservative amino acid substitution, which is likely to impact secondary protein structureas these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a highlyconserved position that is predicted to be within the highly conserved Head region of the GFAP protein. Insilico analysis predicts this variant is probably damaging to the protein structure/function. A missensevariant at the same position (R66Q), as well as missense variants in nearby residues have beenreported in the Human Gene Mutation Database in association with Alexander disease (Stenson et al.,2014), supporting the functional importance of this region of the protein. This is a strong candidatefor a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
Polyphen		0.70	.;P;.;.;.;.;.;.;.
Vest4		0.95, 0.95, 0.94
MutPred		0.86		Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);
MVP		1.0
MPC		0.66
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.99

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: rs797044569; hg19: chr17-42992658;