17-44911246-C-T

Variant names:

• chr17-44911246-C-T
• rs58075601
• NM_002055.5:c.1117G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_002055.5(GFAP):​c.1117G>A​(p.Glu373Lys) 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. 13/22 in silico tools predict a damaging 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. E373A) has been classified as Uncertain significance.

• 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: 7.91
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-44911246-C-T is Pathogenic according to our data. Variant chr17-44911246-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 66439.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.1117G>A	p.Glu373Lys	missense_variant	Exon 6 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1117G>A	p.Glu373Lys	missense_variant	Exon 6 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.1117G>A	p.Glu373Lys	missense_variant	Exon 6 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.1117G>A	p.Glu373Lys	missense_variant	Exon 6 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1117G>A	p.Glu373Lys	missense_variant	Exon 6 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Aug 09, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15732097, 22302460, 12801639, 20301351, 12034785, 18402384) -

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Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Alexander disease Other:1

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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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	.;H;.;.;.;H;H;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	.;.;D;.;.;D;.;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;.;D;.;.;D;.;.;.
Sift4G	Uncertain	0.0020	.;.;D;.;.;D;.;T;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.96, 0.96
MutPred		0.97		Gain of ubiquitination at E373 (P = 0.0162);Gain of ubiquitination at E373 (P = 0.0162);Gain of ubiquitination at E373 (P = 0.0162);.;.;Gain of ubiquitination at E373 (P = 0.0162);Gain of ubiquitination at E373 (P = 0.0162);.;.;
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		-0.00020	Neutral
Varity_R		0.97
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs58075601; hg19: chr17-42988614; COSMIC: COSV53653827; COSMIC: COSV53653827;