17-44915290-C-T

Position:

• chr17-44915290-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002055.5(GFAP):​c.197G>A​(p.Arg66Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,798 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O: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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 17-44915290-C-T is Pathogenic according to our data. 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: {Likely_pathogenic=3, not_provided=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.197G>A	p.Arg66Gln	missense_variant	1/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.197G>A	p.Arg66Gln	missense_variant	1/10		NP_001350775.1
GFAP	NM_001242376.3	c.197G>A	p.Arg66Gln	missense_variant	1/7		NP_001229305.1
GFAP	NM_001131019.3	c.197G>A	p.Arg66Gln	missense_variant	1/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.197G>A	p.Arg66Gln	missense_variant	1/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alexander disease Pathogenic:1 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 14, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with adult-onset Alexander disease [PMID: 22619055, 24188966, 21917775, ClinVar ID: 190332] -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GFAP related disorder (PMID:21917775). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372607). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.887>=0.6). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2023	Published functional studies demonstrate a damaging effect on GFAP assembly and filament formation (Fu et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29421207, 24188966, 22619055, 36088400, 37396762, 32374915, 34012265, 21917775) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2020	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Identified in multiple patients with features consistent with Alexander Disease, including one individual with Rosenthal fibers identified postmortem. Rosenthal fibers are the pathognomonic feature of the astrocyte pathology in Alexander Disease. Thus, this highly specific finding is suggestive of this variants pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D;.;.;.;D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.027	.;.;D;D;.;D;D;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.69, 0.76, 0.84
MutPred		0.83		Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);Loss of MoRF binding (P = 0.0746);
MVP		1.0
MPC		0.58
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.96

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;