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rs267607510

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The NM_002055.5(GFAP):c.209G>A(p.Arg70Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70W) has been classified as Pathogenic.

Frequency

Genomes: đť‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes đť‘“: 0.0000041 ( 0 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

3
6
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2O:2

Conservation

PhyloP100: 4.01
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_002055.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-44915279-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953
PP5
Variant 17-44915278-C-T is Pathogenic according to our data. Variant chr17-44915278-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66461.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GFAPNM_002055.5 linkuse as main transcriptc.209G>A p.Arg70Gln missense_variant 1/9 ENST00000588735.3
GFAPNM_001363846.2 linkuse as main transcriptc.209G>A p.Arg70Gln missense_variant 1/10
GFAPNM_001242376.3 linkuse as main transcriptc.209G>A p.Arg70Gln missense_variant 1/7
GFAPNM_001131019.3 linkuse as main transcriptc.209G>A p.Arg70Gln missense_variant 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GFAPENST00000588735.3 linkuse as main transcriptc.209G>A p.Arg70Gln missense_variant 1/91 NM_002055.5 P1P14136-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251320
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461828
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152352
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.0000240
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:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:2Other:1
not provided, no classification providedliterature onlyEpithelial Biology; Institute of Medical Biology, Singapore-- -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJun 08, 2021Identified in an adult patient with bulbar and/or pseudobulbar signs, ataxia, and brainstem abnormalities, contrast enhancement, and spinal cord abnormalities noted on MRI in the published literature; the variant was absent in the mother however the father was not tested (Caroli et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17894839, 27535533, 20301351, 18684770, 29421207, 26478912, 23430549) -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 03, 2021This missense change has been observed in at least one individual who was not affected with GFAP-related conditions (Invitae). This missense change has been observed in individual(s) with Alexander disease (PMID: 17894839). This variant is present in population databases (rs267607510, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 70 of the GFAP protein (p.Arg70Gln). ClinVar contains an entry for this variant (Variation ID: 66461). 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. This variant disrupts the p.Arg70 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16240361, 17438228, 17894839, 20849398). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -
Uncertain significance, criteria provided, single submitterclinical testingAthena Diagnostics IncMar 15, 2019- -
Alexander disease Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitterclinical testingConcord Molecular Medicine Laboratory, Concord Repatriation General HospitalJan 24, 2023This missense change is one of the common variants causing the adult form of Alexander Disease (PMID: 20301351, 17894839, 18684770, 18495313, 18388212, 24306001). Disease onset is typically in the third decade in described cases with the same variant (PMID: 36088400). This variant is observed in a patient with adult-onset spastic quadriparesis. MRI showed atrophic medulla with narrowed cervical cord. This variant is present in a heterozygous state at a very low frequency in control population (gnomAD). It is located in a mutational hotspot and within the functional IF rod domain in the special “head” region. Another amino acid change in the same codon has been reported as disease causing (ClinVar ID: 66460). In silico analysis by REVEL predicts the effect of the variant as uncertain (REVEL:0.607), MetaRNN as pathogenic (0.953). The current evidence available allows a classification of the variant as “likely pathogenic” (ACMG criteria: PM1, PM5, PS4_moderate, PM2_supporting). -
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Uncertain
0.070
Cadd
Pathogenic
27
Dann
Uncertain
1.0
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.12
FATHMM_MKL
Benign
0.72
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.15
T
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Uncertain
0.66
T
Polyphen
0.18
.;B;.;.;.;.;.;.;.
Vest4
0.28, 0.32, 0.34
MutPred
0.93
Loss of phosphorylation at T65 (P = 0.1906);Loss of phosphorylation at T65 (P = 0.1906);Loss of phosphorylation at T65 (P = 0.1906);Loss of phosphorylation at T65 (P = 0.1906);Loss of phosphorylation at T65 (P = 0.1906);Loss of phosphorylation at T65 (P = 0.1906);Loss of phosphorylation at T65 (P = 0.1906);Loss of phosphorylation at T65 (P = 0.1906);Loss of phosphorylation at T65 (P = 0.1906);
MVP
1.0
MPC
0.73
ClinPred
0.92
D
GERP RS
2.8
Varity_R
0.47
gMVP
0.82

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267607510; hg19: chr17-42992646; COSMIC: COSV99493389; COSMIC: COSV99493389; API