17-44913733-C-T

Position:

• chr17-44913733-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.613G>A​(p.Glu205Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,882 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: 0.0000014 (0 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:2
• Conservation: PhyloP100: 5.04

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 (HGNC:):

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 17-44913733-C-T is Pathogenic according to our data. Variant chr17-44913733-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66488.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.613G>A	p.Glu205Lys	missense_variant	3/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.613G>A	p.Glu205Lys	missense_variant	3/10		NP_001350775.1
GFAP	NM_001242376.3	c.613G>A	p.Glu205Lys	missense_variant	3/7		NP_001229305.1
GFAP	NM_001131019.3	c.613G>A	p.Glu205Lys	missense_variant	3/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.613G>A	p.Glu205Lys	missense_variant	3/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726402

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alexander disease Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 18, 2023	Variant summary: GFAP c.613G>A (p.Glu205Lys) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.613G>A has been reported in the literature in at-least two individuals in a series affected with features of adult onset Alexander Disease (example, Pareyson_2008). However, the authors report that one of these two individuals was asymptomatic, normal neurological examination and no symptoms of Alexander Disease. These data do not allow any conclusion about variant significance. At our laboratory, this variant was observed in an adult individual and the mother, both of whom had clinical and/or MRI findings supporting a diagnosis of Alexander Disease as communicated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Uncertain:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2022	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. Advanced 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 at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 66488). 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: 18684770). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 205 of the GFAP protein (p.Glu205Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;D;.;.;.;.;D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.7	.;M;.;.;M;M;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	.;.;D;.;D;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	.;.;D;.;D;.;.;.
Sift4G	Uncertain	0.0080	.;.;D;.;D;.;D;D
Polyphen		0.68	.;P;.;.;.;.;.;.
Vest4		0.54, 0.55, 0.52
MutPred		0.88		Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);.;Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);
MVP		0.98
MPC		0.91
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.87
gMVP		0.71

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: rs267607507; hg19: chr17-42991101; COSMIC: COSV53649572; COSMIC: COSV53649572;