chr17-44911252-C-T

Position:

• chr17-44911252-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_002055.5(GFAP):​c.1111G>A​(p.Glu371Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. E371G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.91

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 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 17-44911252-C-T is Pathogenic according to our data. Variant chr17-44911252-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1199219.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.1111G>A	p.Glu371Lys	missense_variant	6/9	ENST00000588735.3
GFAP	NM_001363846.2	c.1111G>A	p.Glu371Lys	missense_variant	6/10
GFAP	NM_001242376.3	c.1111G>A	p.Glu371Lys	missense_variant	6/7
GFAP	NM_001131019.3	c.1111G>A	p.Glu371Lys	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.1111G>A	p.Glu371Lys	missense_variant	6/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alexander disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 11, 2020

The GFAP c.1111G>A (p.Glu371Lys) variant is a missense variant located within the Coil 2B region of the alpha-helical rod domain of the protein. The p.Glu371Lys variant has not been reported in the literature in association with Alexander disease. However, three different variants at the same amino acid position have been reported in two studies in individuals affected with Alexander disease (Kawai et al. 2005; Prust et al. 2011). The p.Glu371Lys variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the absence from population frequency databases, the location in a mutational hotspot of a functional domain and the identification in a de novo state, the p.Glu371Lys variant is classified as pathogenic for Alexander disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 30, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 371 of the GFAP protein (p.Glu371Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alexander disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 1199219). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Glu371 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been observed in individuals with GFAP-related conditions (PMID: 16168595, 26478912), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
Polyphen		0.97	.;D;.;.;.;.;.;.;.
Vest4		0.93, 0.93
MutPred		0.89		Gain of ubiquitination at E371 (P = 0.0276);Gain of ubiquitination at E371 (P = 0.0276);Gain of ubiquitination at E371 (P = 0.0276);.;.;Gain of ubiquitination at E371 (P = 0.0276);Gain of ubiquitination at E371 (P = 0.0276);.;.;
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.98
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42988620;