rs57590980

Positions:

• chr17-44915257-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_002055.5(GFAP):​c.230A>G​(p.Asn77Ser) 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N77K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 7.95

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-44915257-T-C is Pathogenic according to our data. Variant chr17-44915257-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 66468.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.230A>G	p.Asn77Ser	missense_variant	1/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.230A>G	p.Asn77Ser	missense_variant	1/10		NP_001350775.1
GFAP	NM_001242376.3	c.230A>G	p.Asn77Ser	missense_variant	1/7		NP_001229305.1
GFAP	NM_001131019.3	c.230A>G	p.Asn77Ser	missense_variant	1/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.230A>G	p.Asn77Ser	missense_variant	1/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 20, 2023	ClinVar contains an entry for this variant (Variation ID: 66468). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn77 amino acid residue in GFAP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23364391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with Alexander disease (PMID: 15732097, 17894839, 26478912). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 77 of the GFAP protein (p.Asn77Ser). -

Alexander disease Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;D;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;H;.;H;H;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.4	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;D;.;D;D;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.88, 0.90, 0.84
MutPred		0.97		Gain of phosphorylation at N77 (P = 0.0191);Gain of phosphorylation at N77 (P = 0.0191);Gain of phosphorylation at N77 (P = 0.0191);Gain of phosphorylation at N77 (P = 0.0191);Gain of phosphorylation at N77 (P = 0.0191);Gain of phosphorylation at N77 (P = 0.0191);Gain of phosphorylation at N77 (P = 0.0191);Gain of phosphorylation at N77 (P = 0.0191);Gain of phosphorylation at N77 (P = 0.0191);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.97

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: rs57590980; hg19: chr17-42992625;