chr17-44910629-T-A

Variant names:

• chr17-44910629-T-A
• rs61726471
• NM_002055.5:c.1157A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_002055.5(GFAP):​c.1157A>T​(p.Asn386Ile) variant causes a missense change involving the alteration of a non-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. N386S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 0.765
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• Alexander disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44910629-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2138057.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76
• PP5: Variant 17-44910629-T-A is Pathogenic according to our data. Variant chr17-44910629-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 66448.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1157A>T	p.Asn386Ile	missense_variant	Exon 7 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1157A>T	p.Asn386Ile	missense_variant	Exon 7 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.1157A>T	p.Asn386Ile	missense_variant	Exon 7 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.1157A>T	p.Asn386Ile	missense_variant	Exon 7 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1157A>T	p.Asn386Ile	missense_variant	Exon 7 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

May 10, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N386I variant has been published previously as an apparently de novo occurrence in association with Alexander disease (Caceres-Marzal et al., 2006). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). N386I is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown N386I disrupts the filament assembly and solubility of the GFAP protein (Chen et al., 2011). Missense variants in the same codon (N386S) nearby residues (T383I, S385F) have been reported in the Human Gene Mutation Database in association with Alexander disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic. -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Alexander disease Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;D;.;.;.;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;T;D;D;T;T;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.5	.;L;.;.;.;L;L;.
PhyloP100		0.77
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	.;.;D;.;.;D;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0050	.;.;D;.;.;D;.;.
Sift4G	Uncertain	0.013	.;.;D;.;.;D;.;D
Polyphen		0.35	.;B;.;.;.;.;.;.
Vest4		0.85, 0.83
MutPred		0.76		Loss of disorder (P = 0.0745);Loss of disorder (P = 0.0745);Loss of disorder (P = 0.0745);.;.;Loss of disorder (P = 0.0745);Loss of disorder (P = 0.0745);.;
MVP		1.0
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.52
gMVP		0.78
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs61726471; hg19: chr17-42987997;