rs267607510

chr17-44915278-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PM1 PM5 PP3_Strong PP5 BS2

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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 O:2
• Conservation: PhyloP100: 4.01

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 Uncertain_significance. Variant got 5 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}.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.209G>A	p.Arg70Gln	missense_variant	1/9	ENST00000588735.3
GFAP	NM_001363846.2	c.209G>A	p.Arg70Gln	missense_variant	1/10
GFAP	NM_001242376.3	c.209G>A	p.Arg70Gln	missense_variant	1/7
GFAP	NM_001131019.3	c.209G>A	p.Arg70Gln	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.209G>A	p.Arg70Gln	missense_variant	1/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

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

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

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

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:2 Uncertain:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2 Other:1

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) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2021	This 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 submitter	clinical testing	Athena Diagnostics	Mar 15, 2019	- -

Alexander disease Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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). -

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

Other links and lift over

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