17-44915278-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP3_StrongPP5BS2

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).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

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]

GFAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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: {Uncertain_significance=2, Likely_pathogenic=2, not_provided=2}.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.209G>A	p.Arg70Gln	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 link	c.209G>A	p.Arg70Gln	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.209G>A	p.Arg70Gln	missense_variant	Exon 1 of 7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 link	c.209G>A	p.Arg70Gln	missense_variant	Exon 1 of 8		NP_001124491.1	P14136-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.209G>A	p.Arg70Gln	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

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:

AN:

251320

Hom.:

AF XY:

0.00

AC XY:

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:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

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:

AN:

152352

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

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

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 02, 2024	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). This variant is present in population databases (rs267607510, gnomAD 0.007%). This missense change has been observed in individual(s) with Alexander disease (PMID: 17894839). This missense change has been observed in at least one individual who was not affected with GFAP-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 66461). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GFAP protein function. 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. 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. -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	Identified 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) -

Alexander disease

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital	Jan 24, 2023	This 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 provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

.;D;.;.;.;D;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.72

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.1

.;M;.;M;M;.;.;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.1

.;.;N;N;.;.;.;.;.

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

.;.;D;D;.;.;.;.;.

Sift4G

Uncertain

0.0030

.;.;D;D;.;D;D;.;.

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over